WO2014045156A1 - Novel bicyclic pyridinones - Google Patents

Novel bicyclic pyridinones Download PDF

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Publication number
WO2014045156A1
WO2014045156A1 PCT/IB2013/058347 IB2013058347W WO2014045156A1 WO 2014045156 A1 WO2014045156 A1 WO 2014045156A1 IB 2013058347 W IB2013058347 W IB 2013058347W WO 2014045156 A1 WO2014045156 A1 WO 2014045156A1
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WIPO (PCT)
Prior art keywords
methyl
mmol
alkyl
phenyl
fluoro
Prior art date
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PCT/IB2013/058347
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English (en)
French (fr)
Inventor
Christopher William Am Ende
Michael Eric GREEN
Douglas Scott Johnson
Gregory Wayne KAUFFMAN
Christopher John O'donnell
Nandini Chaturbhai Patel
Martin Youngjin Pettersson
Antonia Friederike STEPAN
Cory Michael Stiff
Chakrapani Subramanyam
Tuan Phong Tran
Patrick Robert Verhoest
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Pfizer Inc.
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Publication date
Priority to UAA201501621A priority Critical patent/UA110688C2/uk
Priority to MA37886A priority patent/MA37886B1/fr
Priority to RS20161058A priority patent/RS55426B1/sr
Priority to CN201380048982.5A priority patent/CN104662021B/zh
Priority to IN1119DEN2015 priority patent/IN2015DN01119A/en
Priority to KR1020157006971A priority patent/KR101725696B1/ko
Priority to EP13792085.6A priority patent/EP2897956B1/en
Priority to CA2882386A priority patent/CA2882386C/en
Priority to JP2015532539A priority patent/JP5844018B2/ja
Priority to BR112015006436A priority patent/BR112015006436A2/pt
Priority to EA201590319A priority patent/EA026668B1/ru
Priority to MEP-2016-269A priority patent/ME02571B/me
Priority to MYPI2015700772A priority patent/MY181891A/en
Priority to DK13792085.6T priority patent/DK2897956T3/en
Priority to MDA20150023A priority patent/MD4583B1/ru
Priority to SI201330390T priority patent/SI2897956T1/sl
Priority to SG11201501074WA priority patent/SG11201501074WA/en
Application filed by Pfizer Inc. filed Critical Pfizer Inc.
Priority to LTEP13792085.6T priority patent/LT2897956T/lt
Priority to AP2015008277A priority patent/AP2015008277A0/xx
Priority to ES13792085.6T priority patent/ES2609987T3/es
Priority to AU2013319845A priority patent/AU2013319845B2/en
Priority to MX2015003637A priority patent/MX360599B/es
Priority to NZ704863A priority patent/NZ704863A/en
Publication of WO2014045156A1 publication Critical patent/WO2014045156A1/en
Priority to CR20150053A priority patent/CR20150053A/es
Priority to IL237163A priority patent/IL237163A/en
Priority to PH12015500376A priority patent/PH12015500376B1/en
Priority to ZA2015/01195A priority patent/ZA201501195B/en
Priority to TNP2015000084A priority patent/TN2015000084A1/fr
Priority to CUP2015000021A priority patent/CU20150021A7/es
Priority to HK15106474.5A priority patent/HK1206013A1/zh
Priority to HRP20161558TT priority patent/HRP20161558T1/hr
Priority to CY20161101290T priority patent/CY1118662T1/el

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • the present invention relates to the treatment of Alzheimer's disease and other neurodegenerative and/or neurological disorders in mammals, including humans.
  • This invention also relates to the modulation, in mammals, including humans, of the production of A-beta peptides that can contribute to the formation of neurological deposits of amyloid protein. More particularly, this invention relates to novel bicyclic pyridinone compounds useful for the treatment of neurodegenerative and/or
  • neurological disorders such as Alzheimer's disease and Down's Syndrome.
  • AD Alzheimer's disease
  • CM cerebral amyloid angiopathy
  • prion-mediated diseases see, e.g., Haan et al., Clin. Neurol. Neurosurg. 1990, 92(4):305-310; Glenner et al., J. Neurol. Sci. 1989, 94:1 -28.
  • AD affects nearly half of all people past the age of 85, the most rapidly growing portion of the United States population. As such, the number of AD patients in the United States is expected to increase from about 4 million to about 14 million by 2050.
  • the present invention relates to a group of ⁇ -secretase modulators, useful for the treatment of neurodegenerative and/or neurological disorders such as Alzheimer's disease and Down's Syndrome, (see Ann. Rep. Med. Chem. 2007, Olsen et al., 42: 27-47).
  • the present invention is directed to ⁇ -secretase modulators of Formula I or pharmaceutically acceptable salts thereof as represented below: wherein:
  • X is a 5- to 14-mennbered heteroaryl containing 1 -3 heteroatoms
  • R 1 is hydrogen, halogen, d-Cealkyl, C 3 -C 6 cycloalkyl, or C 2 -C 6 alkenyl; wherein said alkyl, cycloalkyi or alkenyl is optionally substituted with one to three substituents each independently selected from the group consisting of fluoro, hydroxyl and C C 6 alkoxy;
  • A is a C 3 -C 6 cycloalkyl or a 4- to 10-membered heterocycloalkyl; wherein said cycloalkyi or heterocycloalkyl is optionally substituted with one to three substituents each independently selected from the group consisting of halogen and C-i-C 6 alkyl;
  • R 2a and R 2b for each occurrence is independently hydrogen, fluoro, cyano, -CF 3 , C-i-C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 6 cycloalkyl, C 4 -C 8 bicycloalkyl, C 2 -C 6 alkynyl or phenyl; wherein said alkyl, alkenyl, cycloalkyi, bicycloalkyl, alkynyl or phenyl is optionally substituted with one to three substituents each independently selected from the group consisting of cyano, Ci_C 3 alkyl and fluoro; or R 2a and R 2b together with the carbon to which they are bonded form a 3- to 5-membered cycloalkyi optionally substituted with one to three of R 8 ;
  • R 3 is hydrogen, halogen, Ci-C 6 alkyl, C 2 -C 6 alkenyl, -(C(R 10 ) 2 ) t -(C 3 -C 6 cycloalkyl), -(C(R 10 ) 2 ) t -(4- to 10-membered heterocycloalkyl), -(C(R 10 ) 2 ) t -(C6-C 10 aryl), -(C(R 10 ) 2 ) t -(5- to 10-membered heteroaryl) or -(C(R 10 ) 2 ) t -OR 12 ; wherein said alkyl, alkenyl, cycloalkyi, heterocycloalkyl, aryl or heteroaryl is optionally substituted with one to five of R 11 ;
  • R 4a and R 4b are each independently hydrogen, -CF 3 , or Ci.C 6 alkyl, wherein said alkyl is optionally substituted with one to three substituents each independently selected from the group consisting of -CF 3 , cyano and fluoro; or R 4a and R 4b together with the carbon to which they are bonded form a 3- to 5-membered cycloalkyi, wherein said cycloalkyl is optionally substituted with one to three substituents each independently selected from the group consisting of -CF 3 , cyano, fluoro and Ci-C6alkyl;
  • R 5a and R 5b for each occurrence are each independently hydrogen, -CF 3 , or C-i- C 6 alkyl, wherein said alkyl is optionally substituted with one to three substituents each independently selected from the group consisting of -CF 3 , cyano and fluoro; or R 5a and R 5b together with the carbon to which they are bonded form a 3- to 5-membered cycloalkyl, wherein said cycloalkyl is optionally substituted with one to three
  • substituents each independently selected from the group consisting of -CF 3 , cyano, fluoro and Ci.C 6 alkyl;
  • R 6 , R 7 and R 8 are each independently hydrogen, -CF 3 , cyano, halogen, d.
  • R 9 is hydrogen, Ci.C 6 alkyl or -CF 3 ; wherein said alkyl is optionally substituted with one to three substituents each independently selected from the group consisting of cyano and fluoro;
  • each R 10 is independently hydrogen, halogen, cyano, -CF 3 , Ci.C 6 alkyl, or -SF 5 ; wherein said alkyl is optionally substituted with one to three fluoro;
  • each R 11 is independently hydrogen, halogen, -CF 3 , -SF 5 , -Si(CH 3 ) 3 , -OR 12 , Ci-
  • each R 12 is hydrogen, d.C ⁇ alkyl, -(C(R 13 ) 2 ) n -(C 3- C 6 cycloalkyl), -(C(R 13 ) 2 ) n -(4- to 10-membered heterocycloalkyl), -(C(R 13 ) 2 ) n -(C 6- Cioaryl), or -(C(R 13 ) 2 ) n -(5- to 10- membered heteroaryl); wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with one to five of R 14 ;
  • each R 13 is independently hydrogen, Ci.C 6 alkyl, C 2- C 6 alkenyl, C 2- C 6 alkynyl, halogen, cyano, -CF 3 , or -OCF 3 ;
  • R 14 is independently hydrogen, -CF 3 , cyano, halogen or Ci -6 alkyl; wherein said alkyl is optionally substituted with one to three substituents each independently selected from the group consisting of hydroxyl, -CF 3 , cyano and fluoro; and
  • each t or n is an integer independently selected from 0, 1 , 2 or 3; each z is an integer independently selected from 1 or 2;
  • each y is an integer independently selected from 0, 1 , 2, 3 or 4.
  • Compounds of the invention include Examples 1 -73 or a pharmaceutically acceptable salt thereof as described herein.
  • compositions comprising a pharmaceutically effective amount of one or more of the compounds described herein and a pharmaceutically acceptable vehicle, carrier or excipient.
  • the compounds of Formula I are ⁇ -secretase modulators. ⁇ -Secretase plays a role
  • the compounds of Formula I are useful in treating a variety of neurodegenerative and/or neurological disorders related to ⁇ production.
  • Ci-C6alkyl refers to a linear or branched-chain saturated hydrocarbyl substituent (i.e., a substituent obtained from a hydrocarbon by removal of a hydrogen) containing from 1 to 6 carbon atoms.
  • substituents include methyl, ethyl, propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, sec- butyl and terf-butyl), pentyl, and hexyl.
  • C-i.Csalkyl refers to a linear or branched-chain saturated hydrocarbyl substituent (i.e., a substituent obtained from a hydrocarbon by removal of a hydrogen) containing from 1 to 3 carbon atoms. Examples of such substituents include methyl, ethyl, and propyl (including n-propyl and isopropyl).
  • C 2- C6alkenyl refers to an aliphatic hydrocarbon containig from 1 to 6 carbon atoms and having at least one carbon-carbon double bond, including straight chain or branched chain groups having at least one carbon-carbon double bond.
  • Representative examples include, but are not limited to, ethenyl, 1 -propenyl, 2- propenyl (allyl), isopropenyl, 2-methyl-1 -propenyl, 1 -butenyl, and 2-butenyl.
  • the compounds of the invention may exist as the pure E (entadel) form, the pure Z (zusammen) form, or any mixture thereof.
  • C 2- C6alkynyl refers to an aliphatic hydrocarbon containing from 2 to 6 carbon atoms and having at least one carbon-carbon triple bond, including straight chain or branched chain groups having at least one carbon-carbon triple bond.
  • Representative examples of an alkynyl include, but are not limited to, to acetylenyl, 1 -propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, and 1 -butynyl.
  • C3-C6cycloalkyl refers to a carbocyclic substituent obtained by removing a hydrogen from a saturated carbocyclic molecule and having 3 to 6 carbon atoms.
  • a cycloalkyl may be a single ring, which typically contains from 3 to 6 ring atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • a cycloalkyl may contain one or more double or triple bonds depending upon the number of carbon atoms contained in the ring (e,g,. cyclohexene has one carbon to carbon double bond or cycloheyne has one carbon to carbon triple bond).
  • a cycloalkyl may be a double ring such as a bicycloalkyl, e.g., C 4 -C8bicycloalkyl.
  • C 4 -C8bicycloalkyl refers to a double ring containing 4 to 8 carbon atoms.
  • the bicycloalkyl may be fused together, such as bicyclo[1 .1 .0]butane,
  • bicycloalkyl also includes bridged bicycloalkyl systems such as, but not limited to, bicyclo[2.2.1 ]heptane and bicyclo[1 .1 .1 ]pentane.
  • C 6 -Ci 0 aryl refers to an aromatic substituent containing from 6 to 10 carbon atoms, including one ring or two fused rings. Examples of such aryl substituents include, but not limited to, phenyl, naphthyl, and dihydroindenyl.
  • hydrogen refers to a hydrogen substituent, and may be depicted as
  • hydroxy or “hydroxyl” refers to -OH.
  • the prefix "hydroxy” indicates that the substituent to which the prefix is attached is substituted with one or more hydroxy substituents.
  • Compounds bearing a carbon to which one or more hydroxy substituents are attached include, for example, alcohols, enols and phenol.
  • cyano also referred to as "nitrile” means -CN, which also may be depicted J c N .
  • halogen refers to fluorine (which may be depicted as -F), chlorine (which may be depicted as -CI), bromine (which may be depicted as -Br), or iodine (which may be depicted as -I).
  • the halogen is chlorine.
  • the halogen is fluorine.
  • the halogen is bromine.
  • (C-i-C6)alkoxy means a (C-i -C6)alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Examples include, but are not limited to, methoxy, ethoxy, and n-propoxy.
  • 4- to 10-membered heterocycloalkyl refers to a substituent obtained by removing a hydrogen from a saturated or partially saturated ring structure
  • heterocycloalkyl containing a total of 4 to 10 ring atoms, wherein at least one of the ring atoms is a heteroatom selected from oxygen, nitrogen, or sulfur.
  • 4- to 10-membered heterocycloalkyls include, but are not limited to, dihydrofuranyl, tetrahydrofuranyl, tetrahydropyranyl, dihydrothiophenyl, and tetrahydrothiophenyl.
  • a heterocycloalkyl alternatively may comprise 2 or 3 rings fused together, wherein at least one such ring contains a heteroatom as a ring atom (i.e., nitrogen, oxygen, or sulfur).
  • the ring atom of the heterocycloalkyl substituent that is bound to the group may be the at least one heteroatom when the heteroatom is nitrogen, or it may be a ring carbon atom, where the ring carbon atom may be in the same ring as the at least one heteroatom or where the ring carbon atom may be in a different ring from the at least one heteroatom.
  • the group or substituent may be bound to the at least one heteroatom when the heteroatom is nitrogen, or it may be bound to a ring carbon atom, where the ring carbon atom may be in the same ring as the at least one heteroatom or where the ring carbon atom may be in a different ring from the at least one heteroatom.
  • 5- to 14-membered heteroaryl refers to an aromatic ring structure containing from 5 to 14 ring atoms in which at least one of the ring atoms is a heteroatom (i.e., oxygen, nitrogen, or sulfur), with the remaining ring atoms being independently selected from the group consisting of carbon, oxygen, nitrogen, and sulfur.
  • a heteroaryl may be a single ring or 2 or 3 fused rings.
  • heteroaryl substituents include but are not limited to: 6-membered ring substituents such as pyridyl, pyrazyl, pyrimidinyl, and pyridazinyl; 5-membered ring substituents such as triazolyl, imidazolyl, furanyl, thiophenyl (also known as "thiofuranyl"), pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, 1 ,2,3-, 1 ,2,4-, 1 ,2,5-, or 1 ,3,4-oxadiazolyl and
  • isothiazolyl 6/5-membered fused ring substituents such as benzothiofuranyl, isobenzothiofuranyl, benzisoxazolyl, benzoxazolyl, purinyl, and anthranilyl; and
  • the ring atom of the heteroaryl substituent that is bound to the group may be the at least one heteroatom when the heteroatom is nitrogen, or it may be a ring carbon atom, where the ring carbon atom may be in the same ring as the at least one heteroatom or where the ring carbon atom may be in a different ring from the at least one
  • heteroaryl also includes pyridyl /V-oxides and groups containing a pyridine /V-oxide ring.
  • a non-hydrogen substituent is in the place of a hydrogen substituent on a carbon or nitrogen of the substituent.
  • a substituted alkyl substituent is an alkyl substituent wherein at least one non-hydrogen substituent is in the place of a hydrogen substituent on the alkyl substituent.
  • monofluoroalkyl is alkyl substituted with a fluoro substituent
  • difluoroalkyl is alkyl substituted with two fluoro substituents. It should be recognized that if there is more than one substitution on a substituent, each non-hydrogen substituent may be identical or different (unless otherwise stated).
  • substituent may be either (1 ) not substituted, or (2) substituted. If a carbon of a substituent is described as being optionally substituted with one or more of a list of substituents, one or more of the hydrogens on the carbon (to the extent there are any) may separately and/or together be replaced with an independently selected optional substituent. If a nitrogen of a substituent is described as being optionally substituted with one or more of a list of substituents, one or more of the hydrogens on the nitrogen (to the extent there are any) may each be replaced with an independently selected optional substituent.
  • a substituent is described as being optionally substituted with up to a particular number of non-hydrogen substituents, that substituent may be either (1 ) not substituted; or (2) substituted by up to that particular number of non-hydrogen substituents or by up to the maximum number of substitutable positions on the substituent, whichever is less.
  • substituent may be either (1 ) not substituted; or (2) substituted by up to that particular number of non-hydrogen substituents or by up to the maximum number of substitutable positions on the substituent, whichever is less.
  • any heteroaryl with less than 3 substitutable positions would be optionally substituted by up to only as many non-hydrogen substituents as the heteroaryl has substitutable positions.
  • tetrazolyl (which has only one substitutable position) would be optionally substituted with up to one non-hydrogen substituent.
  • an amino nitrogen is described as being optionally substituted with up to 2 non- hydrogen substituents, then the nitrogen will be optionally substituted with up to 2 non- hydrogen substituents if the amino nitrogen is a primary nitrogen, whereas the amino nitrogen will be optionally substituted with up to only 1 non-hydrogen substituent if the amino nitrogen is a secondary nitrogen.
  • each substituent is selected independent of the other(s). Each substituent therefore may be identical to or different from the other substituent(s).
  • R 1 any one substituent, such as R 1
  • R 2 any other substituents, such as R 2 , such that each and every combination of the first substituent and the second substituent is provided herein the same as if each combination were specifically and individually listed.
  • R 1 is taken together with R 2 to provide an embodiment wherein R 1 is methyl and R 2 is halogen.
  • the terms "Formula I", “Formula la”, “Formula lb”, and “Formula Ic” may be hereinafter referred to as "compound(s) of the invention.” Such terms are also defined to include all forms of the compound of Formulas I, la, lb, and Ic, including hydrates, solvates, isomers, crystalline and non-crystalline forms, isomorphs, polymorphs, and metabolites thereof.
  • the compounds of Formulas I, la, lb and Ic or pharmaceutically acceptable salts thereof may exist in unsolvated and solvated forms.
  • the solvent or water When the solvent or water is tightly bound, the complex will have a well-defined stoichiometry independent of humidity. When, however, the solvent or water is weakly bound, as in channel solvates and hygroscopic compounds, the water/solvent content will be dependent on humidity and drying conditions. In such cases, non-stoichiometry will be the norm.
  • the compounds of of the invention may exist as clathrates or other complexes.
  • complexes such as clathrates, drug-host inclusion complexes wherein, in contrast to the aforementioned solvates, the drug and host are present in stoichiometric or non-stoichiometric amounts.
  • complexes of Formulas I, la, lb, and Ic containing two or more organic and/or inorganic components which may be in stoichiometric or non-stoichiometric amounts.
  • the resulting complexes may be ionized, partially ionized, or non-ionized.
  • the compounds of the invention may have asymmetric carbon atoms.
  • the carbon-carbon bonds of the compounds of of the invention may be depicted herein using a solid line ( ), a solid wedge ( ⁇ ), or a dotted wedge ( 1 ).
  • the use of a solid line to depict bonds to asymmetric carbon atoms is meant to indicate that all possible stereoisomers (e.g. specific enantiomers, racemic mixtures, etc.) at that carbon atom are included.
  • the use of either a solid or dotted wedge to depict bonds to asymmetric carbon atoms is meant to indicate that the stereoisomer shown is present. When present in racemic comounds, solid and dotted wedges are used to define relative stereochemistry, rather than absolute stereochemistry.
  • Racemic compounds possessing such indicated relative stereochemistry are marked with (+/-).
  • the compounds of of the invention can exist as stereoisomers, which include include cis and trans isomers, optical isomers such as R and S enantiomers, diastereomers, geometric isomers, rotational isomers, and conformational isomers.
  • the compounds of the the invention may exhibit more than one type of isomerism; and mixtures thereof (such as racemates and diastereomeric pairs).
  • acid addition or base addition salts wherein the counterion is optically active, for example, D-lactate or L-lysine, or racemic, for example, DL-tartrate or DL-arginine.
  • the first type is the racemic compound (true racemate) referred to above wherein one homogeneous form of crystal is produced containing both enantiomers in equimolar amounts.
  • the second type is the racemic mixture or conglomerate wherein two forms of crystal are produced in equimolar amounts each comprising a single enantiomer.
  • the present invention also includes isotopically-labeled compounds, which are identical to those recited in Formulas I, la, lb and lc, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that may be incorporated into compounds of of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as, but not limited to, 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 0, 32 P, 35 S, 18 F, and 36 CI.
  • isotopically-labeled compounds of compounds of of the invention for example those into which radioactive isotopes such as 3 H and 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays.
  • Tritiated, i.e., 3 H, and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability.
  • substitution with heavier isotopes such as deuterium, i.e., 2 H can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances.
  • Isotopically-labeled compounds of of the invention may generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples and Preparations below, by substituting an isotopically-labeled reagent for a non-isotopically-labeled reagent.
  • the compounds of this invention may be used in the form of salts derived from inorganic or organic acids.
  • a salt of the compound may be advantageous due to one or more of the salt's physical properties, such as enhanced pharmaceutical stability in differing temperatures and humidities, or a desirable solubility in water or oil.
  • a salt of a compound also may be used as an aid in the isolation, purification, and/or resolution of the compound.
  • the salt preferably is pharmaceutically acceptable.
  • pharmaceutically acceptable salt refers to a salt prepared by combining a compound of formula I with an acid whose anion, or a base whose cation, is generally considered suitable for human consumption.
  • Pharmaceutically acceptable salts are particularly useful as products of the methods of the present invention because of their greater aqueous solubility relative to the parent compound.
  • Suitable pharmaceutically acceptable acid addition salts of the compounds of the present invention when possible include those derived from inorganic acids, such as hydrochloric, hydrobromic, hydrofluoric, boric, fluoroboric, phosphoric,
  • organic acids such as acetic, benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic, glycolic, isothionic, lactic, lactobionic, maleic, malic, methanesulfonic, trifluoromethanesulfonic, succinic, toluenesulfonic, tartaric, and trifluoroacetic acids.
  • Suitable organic acids generally include but are not limited to aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic classes of organic acids.
  • suitable organic acids include but are not limited to acetate, trifluoroacetate, formate, propionate, succinate, glycolate, gluconate, digluconate, lactate, malate, tartaric acid, citrate, ascorbate, glucuronate, maleate, fumarate, pyruvate, aspartate, glutamate, benzoate, anthranilic acid, stearate, salicylate, p-hydroxybenzoate, phenylacetate, mandelate, embonate (pamoate), methanesulfonate, ethanesulfonate, benzenesulfonate, pantothenate,
  • suitable pharmaceutically acceptable salts thereof may include alkali metal salts, i.e., sodium or potassium salts; alkaline earth metal salts, e.g., calcium or magnesium salts; and salts formed with suitable organic ligands, e.g., quaternary ammonium salts.
  • base salts are formed from bases which form non-toxic salts, including aluminum, arginine, benzathine, choline, diethylamine, diolamine, glycine, lysine, meglumine, olamine, tromethamine and zinc salts.
  • Organic salts may be made from secondary, tertiary or quaternary amine salts, such as tromethamine, diethylamine, A/,/V -dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (/V-methylglucamine), and procaine.
  • secondary, tertiary or quaternary amine salts such as tromethamine, diethylamine, A/,/V -dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (/V-methylglucamine), and procaine.
  • Basic nitrogen-containing groups may be quaternized with agents such as lower alkyl (C C6) halides (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides), dialkyl sulfates (i.e., dimethyl, diethyl, dibutyl, and diamyl sulfates), long chain halides (i.e., decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides), arylalkyl halides (i.e., benzyl and phenethyl bromides), and others.
  • C C 6 lower alkyl
  • halides e.g., methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides
  • dialkyl sulfates i.e., dimethyl, diethyl, di
  • hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts.
  • a compound of the invention is administered in an amount effective to treat a condition as described herein.
  • the compounds of the invention are
  • terapéuticaally effective amount refers to that amount of the compound being administered which will relieve to some extent one or more of the symptoms of the disorder being treated.
  • treating means reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition.
  • treatment refers to the act of treating as “treating” is defined immediately above.
  • treating also includes adjuvant and neo-adjuvant treatment of a subject.
  • Formula la depicted below is a subset of Formula I as depicted, wherein z is 1 , and R 5a , R 5b , R 6 and R 7 are each hydrogen.
  • X is a 5-membered heteroaryl selected from imidazolyl, pyrazolyl, isothiazolyl, thiazolyl, isoxazolyl, oxazolyl or pyridyl;
  • R 1 is selected from hydrogen, halogen, or C-i-Csalkyl;
  • y is 0 or 1 ;
  • R 2a and R 2b are each independently hydrogen or C-i-C 3 alkyl;
  • R 4a and R 4b are each independently hydrogen or Ci.C 3 alkyl;
  • A is a C 3 -C 6 cycloalkyl selected from cyclobutyl, cyclopentyl or cyclohexyl, or
  • A is a 5- to 6-membered heterocycloalkyl selected from
  • x is imidazolyl; R 1 is methyl; y is 0; R 2a and R 2b are each independently hydrogen; R 4a and R 4b are each independently hydrogen; A is cyclobutyl; and R 3 is (6,7- difluoronaphthylen-1 -yl)oxy.
  • x is imidazolyl; R 1 is methyl; y is 1 ; one of R 2a or R 2b is hydrogen and the other is methyl; R 4a and R 4b are each independently hydrogen; A is tetrahydrofuranyl; and R 3 is 5- trifluoromethylthiophen-2-yl.
  • Formula lb depicted below is a subset of Formula I as depicted wherein x is imidazolyl, R 3 is phenyl, z is 1 , and R 5a , R 5b , R 6 and R 7 are each hydrogen.
  • R 1 is selected from hydrogen, halogen, or C-i-Csalkyl; y is 0 or 1 ; R 2a and R 2b are independently hydrogen or CrC 3 alkyl; R 4a and R 4b are each
  • A is a C 3 -C 6 cycloalkyl selected from cyclopentyl or cyclohexyl, or A is a 5- to 6-membered heterocycloalkyl selected from
  • cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl or dihydroisoxazolyl are optionally substituted with one to three substituents each independently selected from halogen or CrC 3 alkyl; m is 1 , 2, or 3; and each R 11 is independently selected from hydrogen, fluoro, chloro, -CF 3 , -SF 5 , -OCF 3 , -OCHF 2 , -OCH 3 , -CF 2 CF 3 , -CF 2 CH 3 , or cyclopropyl.
  • R 1 is methyl; y is 1 ; R 2a and R 2b are independently hydrogen; R 4a and R 4b are each independently hydrogen; A is tetrahydropyranyl; m is 1 ; and R 11 is CF 3 .
  • the CF 3 substituent is attached to the phenyl ring at the para position.
  • R 1 is methyl; y is 1 ; R 2a and R 2b are independently hydrogen; R 4a and R 4b are each independently hydrogen; A is cyclohexyl; m is 1 and R 11 is chloro.
  • the chloro substituent is attached to the phenyl ring at the para position.
  • Formula Ic depicted below is a subset of Formula I as depicted wherein x is imidazolyl, R 3 is phenyl, A is tetrahydrofuranyl, z is 1 , and R 5a , R 5b , R 6 and R 7 are each independently hydrogen.
  • R 1 is selected from hydrogen, halogen, or d-Csalkyl
  • R 2a and R 2b are independently hydrogen or methyl
  • R 4a and R 4b are each independently hydrogen or C-i-Csalkyl
  • the tetrahydrofuranyl moiety is optionally substituted with one to three substituents each independently selected from halogen or C-i-C 3 alkyl
  • R 11 is selected from hydrogen, fluoro, chloro, -CF 3 , -SF 5 , - -OCHF2, -OCH3, -CF2CF3, -CF2CH3, or cyclopropyl.
  • R 1 is methyl; R 2a and R 2b are both hydrogen; one of R 4a and R 4b is hydrogen and the other is methyl; and R 11 is -CF 3 .
  • the -CF 3 substituent on the phenyl ring is attached at the para position.
  • R 1 is methyl; R 2a and R 2b are both hydrogen; R 4a and R 4b are both hydrogen; the tetrahydrofuranyl moiety is substituted with a single fluoro or methyl substituent; and R 11 is -CF 3 .
  • the -CF 3 substituent on the phenyl ring is attached at the para position.
  • R 1 is methyl; R 2a and R 2b are both hydrogen; R 4a and R 4b are both hydrogen; and R 11 is fluoro, chloro, -CF 3 , -SF 5 , or -OCH3.
  • R 1 is methyl; one of R 2a and R 2b is hydrogen and the other is methyl; R 2 is hydrogen; R 4a and R 4b are both hydrogen; and R 11 is fluoro, chloro, -CF 3 , -OCF 3 , -OCHF 2 , or - OCH 3 .
  • Formula Id depicted below is a subset of Formula I as depicted wherein x is imidazolyl, A is tetrahydrofuranyl, z is 1 , and R 5a , R 5b , R 6 and R 7 are each independently hydrogen.
  • R 2 is hydrogen or methyl;
  • R 3 is C6-C-ioaryl or a 5- to 6-membered heteroaryl, wherein said aryl or heteroaryl is optionally substituted with one to three R 11 , wherein each R 11 is independently selected from the group consisting of
  • R 3 is phenyl optionally substituted with one to three R 11 substituents independently selected from fluoro, chloro, -CF 3 , -SF 5 , -OCH 3 , -OCF 3 , and -OCHF 2 .
  • thiophenyl optionally substituted with one to three R 11 substituents independently selected from fluoro, chloro, -CF 3 , -SF 5 , -OCH 3 , -OCF 3 , and -OCHF 2 .
  • AD Alheimer's Disease
  • ⁇ - Secretase is a large complex of four different integral proteins, one of which has been identified as the catalytic component that comprises an unusual membrane-embedded component (De Strooper, Bart, et al, "Presenilins and y- Secretase: Structure, Function, and Role in Alzheimer's Disease”Co ⁇ d Spring Harb Perspect Med 2012;2:a006304).
  • the catalytic components known as presenilins were first discovered as sites of missense mutations responsible for early-onset Alzheimer disease (AD).
  • the encoded multipass membrane proteins were first discovered as sites of missense mutations responsible for early-onset Alzheimer disease (AD).
  • ⁇ -secretases membrane- embedded aspartyl protease complexes responsible for generating the carboxyl terminus of the amyloid b-protein ( ⁇ ) from the amyloid protein precursor (APP).
  • APP amyloid protein precursor
  • the compounds of the present invention are ⁇ - secretase modulators and can be used for treating conditions or diseases of the central nervous system identified to have enhanced gamma secretase activity, such as Niemann-Pick type C; neurological disorders (such as migraine; epilepsy; Alzheimer's disease; Parkinson's disease; brain injury; stroke; cerebrovascular diseases (including cerebral arteriosclerosis, cerebral amyloid angiopathy, hereditary cerebral hemorrhage, and brain hypoxia-ischemia); cognitive disorders (including amnesia, senile dementia, HIV-associated dementia, Alzheimer's disease, Huntington's disease, Lewy body dementia, vascular dementia, drug-related dementia, tardive dyskinesia, myoclonus, dystonia, delirium, Pick's disease, Creutzfeldt-Jacob disease, HIV disease, Gilles de la Tourette's syndrome, epilepsy, muscular spasms and disorders associated with muscular spasticity or weakness including tremors, and mild cognitive impairment); mental deficiency
  • anxiety including acute stress disorder, generalized anxiety disorder, social anxiety disorder, panic disorder, posttraumatic stress disorder, agoraphobia, and obsessive-compulsive disorder
  • factitious disorders including acute hallucinatory mania
  • impulse control disorders including compulsive gambling and intermittent explosive disorder
  • mood disorders including bipolar I disorder, bipolar II disorder, mania, mixed affective state, major depression, chronic depression, seasonal depression, psychotic depression, seasonal depression, premenstrual syndrome (PMS) premenstrual dysphoric disorder (PDD), and postpartum depression
  • psychomotor disorders including psychotic disorders (including schizophrenia, schizoaffective disorder, schizophreniform, and delusional disorder); drug dependence (including narcotic dependence, alcoholism, amphetamine dependence, cocaine addiction, nicotine dependence, and drug withdrawal syndrome); eating disorders (including anorexia, bulimia, binge eating disorder,
  • a mammal preferably a human
  • administering comprising administering to said mammal a therapeutically effective amount of a compound of Formula I, Formula la, Formula lb, and Formula Ic or a pharmaceutically acceptable salt thereof.
  • the compounds of the present invention can be utilized for treating a neurological disorder (such as migraine; epilepsy; Alzheimer's disease; Parkinson's disease; Niemann Pick type C; brain injury; stroke; cerebrovascular disease; cognitive disorder; sleep disorder) or a psychiatric disorder (such as anxiety; factitious disorder; impulse control disorder; mood disorder; psychomotor disorder; psychotic disorder; drug dependence; eating disorder; and pediatric psychiatric disorder) in a mammal, preferably a human, comprising administering to said mammal a therapeutically effective amount of a compound of Formula I or pharmaceutically acceptable salt thereof.
  • a neurological disorder such as migraine; epilepsy; Alzheimer's disease; Parkinson's disease; Niemann Pick type C; brain injury; stroke; cerebrovascular disease; cognitive disorder; sleep disorder
  • a psychiatric disorder such as anxiety; factitious disorder; impulse control disorder; mood disorder; psychomotor disorder; psychotic disorder; drug dependence; eating disorder; and pediatric psychiatric disorder
  • Compounds of the present invention may also be useful for improving memory (both short term and long term) and learning ability.
  • the compounds of the invention may be administered orally. Oral
  • administration may involve swallowing, so that the compound enters the
  • gastrointestinal tract, or buccal or sublingual administration may be employed by which the compound enters the blood stream directly from the mouth.
  • the compounds of the invention may also be any organic compound.
  • the compounds of the invention may also be any organic compound.
  • Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular and subcutaneous.
  • Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques.
  • the compounds of the invention may also be any organic compound.
  • the compounds of the invention may also be any organic compound.
  • the compounds of the invention can also be administered intranasally or by inhalation.
  • the compounds of the invention may be administered rectally or vaginally.
  • the compounds of the invention may also be administered directly to the eye or ear.
  • the dosage regimen for the compounds and/or compositions containing the compounds is based on a variety of factors, including the type, age, weight, sex and medical condition of the patient; the severity of the condition; the route of
  • the dosage regimen may vary widely. Dosage levels of the order from about 0.01 mg to about 100 mg per kilogram of body weight per day are useful in the treatment of the above-indicated conditions.
  • the total daily dose of a compound of the invention is typically from about 0.01 to about 100 mg/kg.
  • the total daily dose of the compound of the invention is from about 0.1 to about 50 mg/kg, and in another embodiment, from about 0.5 to about 30 mg/kg (i.e., mg compound of the invention per kg body weight). In one embodiment, dosing is from 0.01 to 10 mg/kg/day.
  • dosing is from 0.1 to 1 .0 mg/kg/day.
  • Dosage unit compositions may contain such amounts or submultiples thereof to make up the daily dose.
  • the administration of the compound will be repeated a plurality of times in a day (typically no greater than 4 times). Multiple doses per day typically may be used to increase the total daily dose, if desired.
  • compositions may be provided in the form of tablets containing 0.01 , 0.05, 0.1 , 0.5, 1 .0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 75.0, 100, 125, 150, 175, 200, 250 and 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient.
  • a medicament typically contains from about 0.01 mg to about 500 mg of the active ingredient, or in another embodiment, from about 1 mg to about 100 mg of active ingredient.
  • doses may range from about 0.1 to about 10 mg/kg/minute during a constant rate infusion.
  • Suitable subjects according to the present invention include mammalian subjects. Mammals according to the present invention include, but are not limited to, canine, feline, bovine, caprine, equine, ovine, porcine, rodents, lagomorphs, primates, and the like, and encompass mammals in utero. In one embodiment, humans are suitable subjects. Human subjects may be of either gender and at any stage of development.
  • the invention comprises the use of one or more compounds of the invention for the preparation of a medicament for the treatment of the conditions recited herein.
  • the compounds of the invention can be administered as compound per se.
  • pharmaceutically acceptable salts are suitable for medical applications because of their greater aqueous solubility relative to the parent compound.
  • the present invention comprises pharmaceutical compositions.
  • Such pharmaceutical compositions comprise a compound of the invention presented with a pharmaceutically acceptable carrier.
  • the carrier can be a solid, a liquid, or both, and may be formulated with the compound as a unit-dose composition, for example, a tablet, which can contain from 0.05% to 95% by weight of the active compounds.
  • a compound of the invention may be coupled with suitable polymers as targetable drug carriers. Other pharmacologically active substances can also be present.
  • the compounds of the present invention may be administered by any suitable route, preferably in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment intended.
  • the active compounds and compositions for example, may be administered orally, rectally, parenterally, or topically.
  • Oral administration of a solid dose form may be, for example, presented in discrete units, such as hard or soft capsules, pills, cachets, lozenges, or tablets, each containing a predetermined amount of at least one compound of the present invention.
  • the oral administration may be in a powder or granule form.
  • the oral dose form is sub-lingual, such as, for example, a lozenge.
  • the compounds of formula I are ordinarily combined with one or more adjuvants.
  • Such capsules or tablets may contain a controlled-release formulation.
  • the dosage forms also may comprise buffering agents or may be prepared with enteric coatings.
  • oral administration may be in a liquid dose form.
  • Liquid dosage forms for oral administration include, for example, pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art (i.e., water).
  • Such compositions also may comprise adjuvants, such as wetting, emulsifying, suspending, flavoring (e.g., sweetening), and/or perfuming agents.
  • the present invention comprises a parenteral dose form.
  • Parenteral administration includes, for example, subcutaneous injections, intravenous injections, intraperitoneal injections, intramuscular injections, intrasternal injections, and infusion.
  • injectable preparations i.e., sterile injectable aqueous or oleaginous suspensions
  • suitable dispersing, wetting, and/or suspending agents may be formulated according to the known art using suitable dispersing, wetting, and/or suspending agents.
  • Topical administration includes, for example, transdermal administration, such as via transdermal patches or iontophoresis devices, intraocular administration, or intranasal or inhalation administration.
  • Compositions for topical administration also include, for example, topical gels, sprays, ointments, and creams.
  • a topical formulation may include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas.
  • Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibres, bandages and microemulsions. Liposomes may also be used.
  • Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol.
  • Penetration enhancers may be incorporated - see, for example, Finnin and Morgan, J. Pharm. Sci., 88 (10), 955-958 (1999).
  • Formulations suitable for topical administration to the eye include, for example, eye drops wherein the compound of this invention is dissolved or suspended in a suitable carrier.
  • a typical formulation suitable for ocular or aural administration may be in the form of drops of a micronised suspension or solution in isotonic, pH-adjusted, sterile saline.
  • Other formulations suitable for ocular and aural administration include ointments, biodegradable (i.e., absorbable gel sponges, collagen) and nonbiodegradable (i.e., silicone) implants, wafers, lenses and particulate or vesicular systems, such as niosomes or liposomes.
  • a polymer such as crossed-l inked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, a cellulosic polymer, for example, hydroxypropylmethylcellulose, hydroxyethylcellulose, or methylcellulose, or a heteropolysaccharide polymer, for example, gelan gum, may be incorporated together with a preservative, such as benzalkonium chloride.
  • a preservative such as benzalkonium chloride.
  • Such formulations may also be delivered by iontophoresis.
  • the active compounds of the invention are conveniently delivered in the form of a solution or suspension from a pump spray container that is squeezed or pumped by the patient or as an aerosol spray presentation from a pressurized container or a nebulizer, with the use of a suitable propellant.
  • Formulations suitable for intranasal administration are typically administered in the form of a dry powder (either alone; as a mixture, for example, in a dry blend with lactose; or as a mixed component particle, for example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler or as an aerosol spray from a pressurised container, pump, spray, atomiser (preferably an atomiser using electrohydrodynamics to produce a fine mist), or nebuliser, with or without the use of a suitable propellant, such as 1 ,1 ,1 ,2-tetrafluoroethane or
  • the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin.
  • the present invention comprises a rectal dose form.
  • Such rectal dose form may be in the form of, for example, a suppository. Cocoa butter is a traditional suppository base, but various alternatives may be used as appropriate.
  • compositions of the invention may be prepared by any of the well-known techniques of pharmacy, such as effective formulation and administration procedures.
  • effective formulations and administration procedures are well known in the art and are described in standard textbooks.
  • Formulation of drugs is discussed in, for example, Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania, 1975; Liberman et al., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Kibbe et al., Eds., Handbook of
  • the compounds of the present invention can be used, alone or in combination with other therapeutic agents, in the treatment of various conditions or disease states.
  • the compound(s) of the present invention and other therapeutic agent(s) may be administered simultaneously (either in the same dosage form or in separate dosage forms) or sequentially.
  • An exemplary therapeutic agent may be, for example, a metabotropic glutamate receptor agonist.
  • the administration of two or more compounds "in combination” means that the two compounds are administered closely enough in time that the presence of one alters the biological effects of the other.
  • the two or more compounds may be administered simultaneously, concurrently or sequentially. Additionally, simultaneous administration may be carried out by mixing the compounds prior to administration or by administering the compounds at the same point in time but at different anatomic sites or using different routes of administration.
  • simultaneous administration may be carried out by mixing the compounds prior to administration or by administering the compounds at the same point in time but at different anatomic sites or using different routes of administration.
  • the phrases “concurrent administration,” “co-administration,” “simultaneous administration,” and “administered simultaneously” mean that the compounds are administered in combination.
  • the present invention includes the use of a combination of a ⁇ -secretase modulator compound as provided in Formula I and one or more additional
  • the present invention also includes pharmaceutical compositions comprising an amount of: (a) a first agent comprising a compound of Formula I or a pharmaceutically acceptable salt of the compound; (b) a second pharmaceutically active agent; and (c) a pharmaceutically acceptable carrier, vehicle or diluent.
  • compositions of the present invention include, without limitation:
  • acetylcholinesterase inhibitors such as donepezil hydrochloride (ARICEPT, MEMAC), physostigmine salicylate (ANTILIRIUM), physostigmine sulfate (ESERINE), metrifonate, neostigmine, ganstigmine, pyridostigmine (MESTINON), ambenonium (MYTELASE), demarcarium, Debio 9902 (also known as ZT-1 ; Debiopharm), rivastigmine (EXELON), ladostigil, NP-0361 , galantamine hydrobromide (RAZADYNE, RIMINYL, NIVALIN), tacrine (COGNEX), tolserine, velnacrine maleate, memoquin, huperzine A (HUP-A; NeuroHitech), phenserine, edrophonium (ENLON, TENSILON), and INM-176;
  • amyloid- ⁇ (or fragments thereof), such as ⁇ _ ⁇ 5 conjugated to pan HLA DR- binding epitope (PADRE), ACC-001 (Elan/Wyeth), ACI-01 , ACI-24, AN-1792, Affitope AD-01 , CAD106, and V-950;
  • antibodies to amyloid- ⁇ such as ponezumab, solanezumab, bapineuzumab (also known as AAB-001 ), AAB-002 (Wyeth/Elan), ACI- 01 -Ab7, BAN-2401 , intravenous Ig (GAMMAGARD), LY2062430 (humanized m266; Lilly), R1450 (Roche), ACU-5A5, huC091 , and those disclosed in International Patent Publication Nos WO04/032868, WO05/025616, WO06/036291 , WO06/069081 , WO06/1 18959, in US Patent Publication Nos US2003/0073655, US2004/0192898, US2005/0048049, US2005/0019328, in European Patent Publication Nos EP0994728 and 1257584, and in US Patent No 5,750,349;
  • amyloid-lowering or -inhibiting agents including those that reduce amyloid production, accumulation and fibrillization
  • amyloid-lowering or -inhibiting agents such as dimebon, davunetide, eprodisate, leuprolide, SK-PC-B70M, celecoxib, lovastatin, anapsos, oxiracetam, pramiracetam, varenicline, nicergoline, colostrinin, bisnorcymserine (also known as BNC), NIC5-15 (Humanetics), E-2012 (Eisai), pioglitazone, clioquinol (also known as PBT1 ), PBT2 (Prana Biotechnology), flurbiprofen (ANSAID, FROBEN) and its R-enantiomer tarenflurbil (FLURIZAN), nitroflurbiprofen, fenoprofen (FENOPRON, NALFON), ibuprofen
  • Secretase Modulators such as ELND-007; and RAGE (receptor for advanced glycation end-products) inhibitors, such as TTP488 (Transtech) and TTP4000 (Transtech), and those disclosed in US Patent No 7,285,293, including PTI-777;
  • alpha-adrenergic receptor agonists such as guanfacine (INTUNIV, TENEX), clonidine (CATAPRES), metaraminol (ARAMINE), methyldopa (ALDOMET, DOPAMET, NOVOMEDOPA), tizanidine (ZANAFLEX), phenylephrine (also known as
  • neosynephrine methoxamine
  • cirazoline guanfacine
  • lofexidine lofexidine
  • xylazine modafinil
  • PROVIGIL modafinil
  • NUVIGIL armodafinil
  • beta-adrenergic receptor blocking agents such as carteolol, esmolol (BREVIBLOC), labetalol (NORMODYNE, TRANDATE), oxprenolol (LARACOR, TRASACOR), pindolol (VISKEN), propanolol (INDERAL), sotalol (BETAPACE,
  • anticholinergics such as amitriptyline (ELAVIL, ENDEP), butriptyline, benztropine mesylate (COGENTIN), trihexyphenidyl (ARTANE), diphenhydramine (BENADRYL), orphenadrine (NORFLEX), hyoscyamine, atropine (ATROPEN), scopolamine (TRANSDERM-SCOP), scopolamine methylbromide (PARMINE), dicycloverine (BENTYL, BYCLOMINE, DIBENT, DILOMINE), tolterodine (DETROL), oxybutynin (DITROPAN, LYRINEL XL, OXYTROL), penthienate bromide, propantheline (PRO-BANTHINE), cyclizine, imipramine hydrochloride (TOFRANIL), imipramine maleate (SURMONTIL), lofepramine, desipramine (NORPRAMIN),
  • anticonvulsants such as carbamazepine (TEGRETOL, CARBATROL), oxcarbazepine (TRILEPTAL), phenytoin sodium (PHENYTEK), fosphenytoin
  • DEPAKENE valproate sodium
  • DEPACON 1 -benzyl-5-bromouracil
  • progabide beclamide
  • zonisamide TRERIEF, EXCEGRAN
  • CP-465022 retigabine
  • talampanel retigabine
  • primidone MYSOLINE
  • ix antipsychotics such as lurasidone (LATUDA, also known as SM-13496; Dainippon Sumitomo), aripiprazole (ABILIFY), chlorpromazine (THORAZINE), haloperidol (HALDOL), iloperidone (FANAPTA), flupentixol decanoate (DEPIXOL, FLUANXOL), reserpine (SERPLAN), pimozide (ORAP), fluphenazine decanoate, fluphenazine hydrochloride, prochlorperazine (COMPRO), asenapine (SAPHRIS), loxapine (LOXITANE), molindone (MOBAN), perphenazine, thioridazine, thiothixine, trifluoperazine (STELAZINE), ramelteon, clozapine (CLOZARIL), norclozapine (ACP- 104), risperidone (RISPER
  • (x) calcium channel blockers such as lomerizine, ziconotide, nilvadipine
  • catechol O-methyltransferase (COMT) inhibitors such as nitecapone, tolcapone (TASMAR), entacapone (COMTAN), and tropolone;
  • central nervous system stimulants such as atomoxetine, reboxetine, yohimbine, caffeine, phenmetrazine, phendimetrazine, pemoline, fencamfamine
  • GLUCOENERGAN REACTIVAN
  • fenethylline CAPTAGON
  • pipradol MEMRAN
  • deanol also known as dimethylaminoethanol
  • DAYTRANA methylphenidate
  • RITALIN methylphenidate hydrochloride
  • dexmethylphenidate FOCALIN
  • amphetamine (alone or in combination with other CNS stimulants, e.g. ADDERALL (amphetamine aspartate, amphetamine sulfate, dextroamphetamine saccharate, and dextroamphetamine sulfate)), dextroamphetamine sulfate (DEXEDRINE,
  • DEXTROSTAT methamphetamine
  • VYVANSE lisdexamfetamine
  • DIDREX benzphetamine
  • corticosteroids such as prednisone (STERAPRED, DELTASONE), prednisolone (PRELONE), predisolone acetate (OMNIPRED, PRED MILD, PRED FORTE), prednisolone sodum phosphate (ORAPRED ODT), methylprednisolone (MEDROL); methylprednisolone acetate (DEPO-MEDROL), and methylprednisolone sodium succinate (A-METHAPRED, SOLU-MEDROL);
  • dopamine receptor agonists such as apomorphine (APOKYN)
  • PARLODEL bromocriptine
  • DOSTINEX cabergoline
  • dihydrexidine dihydrexidine
  • dihydroergocryptine dihydroergocryptine, fenoldopam (CORLOPAM), lisuride (DOPERGIN), terguride spergolide (PERMAX), piribedil (TRIVASTAL, TRASTAL), pramipexole (MIRAPEX), quinpirole, ropinirole (REQUIP), rotigotine (NEUPRO), SKF-82958 (GlaxoSmithKline), cariprazine, pardoprunox and sarizotan;
  • dopamine receptor antagonists such as chlorpromazine, fluphenazine, haloperidol, loxzpine, resperidone, thioridazine, thiothixene, trifluoperazine,
  • tetrabenazine NITOMAN, XENAZINE
  • 7-hydroxyamoxapine droperidol
  • INAPSINE DRIDOL, DROPLETAN
  • domperidone MOTILIUM
  • L-741742, L-745870, raclopride SB-27701 1A
  • SCH-23390 ecopipam
  • SKF-83566 metoclopramide
  • dopamine reuptake inhibitors such as bupropion, safinamide, nomifensine maleate (MERITAL), vanoxerine (also known as GBR-12909) and its decanoate ester DBL-583, and amineptine;
  • GABA gamma-amino-butyric acid receptor agonists
  • baclofen LIORESAL, KEMSTRO
  • siclofen pentobarbital
  • NEMBUTAL pentobarbital
  • GABRENE progabide
  • clomethiazole gamma-amino-butyric acid receptor agonists
  • histamine 3 (H3) antagonists such as ciproxifan, tiprolisant, S-38093, irdabisant, pitolisant, GSK-239512, GSK-207040, JNJ-5207852, JNJ-17216498, HPP- 404, SAR-1 10894, trans-3-fluoro-3-(3-fluoro-4-pyrrolidin-1 -ylmethyl-phenyl)- cyclobutane carboxylic acid ethylamide (PF-3654746 and those disclosed in US Patent Publication Nos US2005-0043354, US2005-0267095, US2005-0256135, US2008- 0096955, US2007-1079175, and US2008-0176925; International Patent Publication Nos WO2006/136924, WO2007/063385, WO2007/069053, WO2007/088450,
  • (xix) immunomodulators such as glatiramer acetate (also known as copolymer-1 ; COPAXONE), MBP-8298 (synthetic myelin basic protein peptide), dimethyl fumarate, fingolimod (also known as FTY720), roquinimex (LINOMIDE), laquinimod (also known as ABR-215062 and SAIK-MS), ABT-874 (human anti-IL-12 antibody; Abbott), rituximab (RITUXAN), alemtuzumab (CAMPATH), daclizumab (ZENAPAX), and natalizumab (TYSABRI);
  • glatiramer acetate also known as copolymer-1 ; COPAXONE
  • MBP-8298 synthetic myelin basic protein peptide
  • dimethyl fumarate fingolimod
  • LINOMIDE roquinimex
  • laquinimod also known as ABR-215062 and SAIK-
  • immunosuppressants such as methotrexate (TREXALL, RHEUMATREX), mitoxantrone (NOVANTRONE), mycophenolate mofetil (CELLCEPT), mycophenolate sodium (MYFORTIC), azathioprine (AZASAN, IMURAN), mercaptopurine (PURI- NETHOL), cyclophosphamide (NEOSAR, CYTOXAN), chlorambucil (LEUKERAN), cladribine (LEUSTATIN, MYLINAX), alpha-fetoprotein, etanercept (ENBREL), and 4- benzyloxy-5-((5-undecyl-2H-pyrrol-2-ylidene)methyl)-2,2'-bi-1 H-pyrrole (also known as PNU-156804);
  • TREXALL methotrexate
  • RHEUMATREX mitoxantrone
  • NOVANTRONE mycophenolate mofetil
  • interferons including interferon beta-1 a (AVONEX, REBIF) and interferon beta-1 b (BETASERON, BETAFERON);
  • levodopa or its methyl or ethyl ester
  • a DOPA decarboxylase inhibitor e.g. carbidopa (SINEMET, CARBILEV, PARCOPA), benserazide (MADOPAR), a-methyldopa, monofluromethyldopa, difluoromethyldopa, brocresine, or m-hydroxybenzylhydrazine
  • DOPA decarboxylase inhibitor e.g. carbidopa (SINEMET, CARBILEV, PARCOPA), benserazide (MADOPAR), a-methyldopa, monofluromethyldopa, difluoromethyldopa, brocresine, or m-hydroxybenzylhydrazine
  • NAMENDA AXURA, EBIXA
  • SYMMETREL amantadine
  • CAMPRAL acamprosate
  • besonprodil ketamine (KETALAR)
  • delucemine dexanabinol
  • dexefaroxan dexefaroxan
  • MAO monoamine oxidase inhibitors
  • EMSAM selegiline
  • l-deprenyl ELDEPRYL
  • ZELAPAR ZELAPAR
  • dimethylselegilene brofaromine
  • NARDIL phenelzine
  • PARNATE tranylcypromine
  • AURORIX, MANERIX befloxatone, safinamide, isocarboxazid (MARPLAN), nialamide (NIAMID), rasagiline (AZILECT), iproniazide (MARSILID, IPROZID, IPRONID), CHF- 3381 (Chiesi Farmaceutici), iproclozide, toloxatone (HUMORYL, PERENUM), bifemelane, desoxypeganine, harmine (also known as telepathine or banasterine), harmaline, linezolid (ZYVOX, ZYVOXID), and pargyline (EUDATIN, SUPIRDYL);
  • muscarinic receptor particularly M1 subtype agonists, such as cevimeline, levetiracetam, bethanechol chloride (DUVOID, URECHOLINE), itameline, pilocarpine (SALAGEN), NGX267, arecoline, L-687306 (Merck), L-689660 (Merck), furtrethonium iodide (FURAMON, FURANOL), furtrethonium benzensulfonate, furtrethonium p- toluenesulfonate, McN-A-343, oxotremorine, sabcomeline, AC-90222 (Acadia) muscarinic receptor (particularly M1 subtype) agonists, such as cevimeline, levetiracetam, bethanechol chloride (DUVOID, URECHOLINE), itameline, pilocarpine (SALAGEN), NGX267, arecoline, L-687306 (Merck), L-689660
  • neuroprotective drugs such as bosutinib, condoliase, airmoclomol, lamotrigine, perampanel, aniracetam, minaprime, viluzole 2,3,4,9-tetrahydro-I H- carbazol-3-one oxime, desmoteplase, anatibant, astaxanthin, neuropeptide NAP (e.g.
  • ADNF-14 National Institutes of Health
  • stilbazulenyl nitrone SUN- N8075 (Daiichi Suntory Biomedical Research), and zonampanel;
  • nicotinic receptor agonists such as epibatidine, bupropion, CP-601927, varenicline, ABT-089 (Abbott), ABT-594, AZD-0328 (AstraZeneca), EVP-6124, R3487 (also known as MEM3454; Roche/Memory Pharmaceuticals), R4996 (also known as MEM63908; Roche/Memory Pharmaceuticals), TC-4959 and TC-5619 (both Targacept), and RJR-2403;
  • nicotinic receptor agonists such as epibatidine, bupropion, CP-601927, varenicline, ABT-089 (Abbott), ABT-594, AZD-0328 (AstraZeneca), EVP-6124, R3487 (also known as MEM3454; Roche/Memory Pharmaceuticals), R4996 (also known as MEM63908; Roche/Memory Pharmaceuticals), TC-4959 and TC-5619
  • norepinephrine (noradrenaline) reuptake inhibitors such as atomoxetine (STRATTERA), doxepin (APONAL, ADAPIN, SINEQUAN), nortriptyline (AVENTYL, PAMELOR, NORTRILEN), amoxapine (ASENDIN, DEMOLOX, MOXIDIL), reboxetine (ED RON AX, VESTRA), viloxazine (VIVALAN), maprotiline (DEPRILEPT, LUDIOMIL, PSYMION), bupropion (WELLBUTRIN), and radaxafine;
  • atomoxetine STRATTERA
  • doxepin APIONAL, ADAPIN, SINEQUAN
  • nortriptyline AVENTYL, PAMELOR, NORTRILEN
  • amoxapine ASENDIN, DEMOLOX, MOXIDIL
  • reboxetine ED RON AX, VESTRA
  • PDE phosphodiesterase
  • PDE1 inhibitors e.g. vinpocetine (CAVINTON, CERACTIN, INTELECTOL) and those disclosed in US Patent No 6,235,742
  • PDE2 inhibitors e.g. erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA), BAY 60-7550, and those described in US Patent No. 6,174,884
  • PDE3 inhibitors e.g. anagrelide, cilostazol, milrinone, olprinone, parogrelil, and pimobendan
  • PDE4 inhibitors e.g.
  • apremilast ibudilastroflumilast, rolipram, Ro 20-1724, ibudilast (KETAS), piclamilast (also known as RP73401 ), CDP840, cilomilast (ARIFLO), roflumilast, tofimilast, oglemilast (also known as GRC 3886), tetomilast (also known as OPC-6535), lirimifast, theophylline (UNIPHYL, THEOLAIR), arofylline (also known as LAS-31025), doxofylline, RPR-122818, or mesembrine), and (e) PDE5 inhibitors (e.g.
  • sildenafil VIAGRA, REVATIO
  • tadalafil CIALIS
  • vardenafil LEVITRA, VIVANZA
  • udenafil avanafil
  • dipyridamole PERSANTINE
  • PDE9 inhibitors e.g. BAY 73-6691 (Bayer AG) and those disclosed in US Patent Publication Nos
  • PDE10 inhibitor such as 2-[4-(1 -Methyl-4- pyridin-4-yl-1 H-pyrazol-3-yl)phenoxymethyl]quinoline (PF-2545920), and SCH-1518291 ;
  • quinolines such as quinine (including its hydrochloride, dihydrochloride, sulfate, bisulfate and gluconate salts), chloroquine, thankoquine, hydroxychloroquine (PLAQUENIL), mefloquine (LARIAM), and amodiaquine (CAMOQUIN, FLAVOQUINE);
  • ⁇ -secretase inhibitors such as ASP-1702, SCH-745966, JNJ-715754, AMG-0683, AZ-12304146, BMS-782450, GSK-188909, NB-533, LY-2886721 , E-2609, HPP-854, (+)-phenserine tartrate (POSIPHEN), LSN-2434074 (also known as LY- 2434074), KMI-574, SCH-745966, Ac-rER (N 2 -acetyl-D-arginyl-L-arginine), loxistatin (also known as E64d), and CA074Me;
  • POSIPHEN (+)-phenserine tartrate
  • LSN-2434074 also known as LY- 2434074
  • KMI-574 SCH-745966
  • Ac-rER N 2 -acetyl-D-arginyl-L-arginine
  • loxistatin also known as E64d
  • ⁇ -secretase inhibitors and modulators such as BMS-708163 (Avagacest), WO20060430064 (Merck), DSP8658 (Dainippon), ITI-009, L-685458 (Merck), ELAN-G, ELAN-Z, 4-chloro-/V-[2-ethyl-1 (S)-(hydroxymethyl)butyl]benzenesulfonamide;
  • (xxxiii) serotonin (5-hydroxytryptamine) 1A (5-HTi A ) receptor antagonists such as spiperone, /evo-pindolol, BMY 7378, NAD-299, S(-)-UH-301 , NAN 190, lecozotan;
  • (xxxvi) serotonin (5-hydroxytryptamine) 6 (5-HT 6 ) receptor antagonists such as A-964324, AVI-101 , AVN-21 1 , mianserin (TORVOL, BOLVIDON, NORVAL),
  • methiothepin also known as metitepine
  • ritanserin ALX-1 161 , ALX-1 175, MS-245, LY- 483518 (also known as SGS518; Lilly), MS-245, Ro 04-6790, Ro 43-68544, Ro 63- 0563, Ro 65-7199, Ro 65-7674, SB-399885, SB-2141 1 1 , SB-258510, SB-271046, SB- 357134, SB-699929, SB-271046, SB-742457 (GlaxoSmithKline), Lu AE58054
  • serotonin (5-HT) reuptake inhibitors such as alaproclate, citalopram (CELEXA, CIPRAMIL), escitalopram (LEXAPRO, CIPRALEX), clomipramine
  • ANAFRANIL duloxetine
  • CYMBALTA duloxetine
  • MALEXIL femoxetine
  • trophic factors such as nerve growth factor (NGF), basic fibroblast growth factor (bFGF; ERSOFERMIN), neurotrophin-3 (NT-3), cardiotrophin-1 , brain- derived neurotrophic factor (BDNF), neublastin, meteorin, and glial-derived neurotrophic factor (GDNF), and agents that stimulate production of trophic factors, such as propentofylline, idebenone, PYM50028 (COGANE; Phytopharm), and AIT-082
  • NGF nerve growth factor
  • bFGF basic fibroblast growth factor
  • ERSOFERMIN neurotrophin-3
  • cardiotrophin-1 a neurotrophic factor
  • BDNF brain- derived neurotrophic factor
  • GDNF glial-derived neurotrophic factor
  • agents that stimulate production of trophic factors such as propentofylline, idebenone, PYM50028 (COGANE; Phytopharm), and AIT-082
  • Glycine transporter-1 inhibitors such as paliflutine, ORG-25935, JNJ- 17305600, and ORG-26041 ;
  • AMPA-type glutamate receptor modulators such as perampanel, mibampator, selurampanel, GSK-729327, and N-((3S, 4S)-4-(4-(5-cyanothiophen-2-yl)phenoxy) tetrahydrofuran-3-yl)propane-2-sulfonamide;
  • the present invention further comprises kits that are suitable for use in
  • the kit contains a first dosage form comprising one or more of the compounds of the present invention and a container for the dosage, in quantities sufficient to carry out the methods of the present invention.
  • kit of the present invention comprises one or more compounds of the invention.
  • the compounds of Formula I, Formula la, Formula lb and Formula lc, or their pharmaceutically acceptable salts may be prepared by the methods described below, together with synthetic methods known in the art of organic chemistry, or modifications and derivatizations that are familiar to those of ordinary skill in the art.
  • the starting materials used herein are commercially available or may be prepared by routine methods known in the art (such as those methods disclosed in standard reference books such as the COMPENDIUM OF ORGANIC SYNTHETIC METHODS, Vol. I-XII (published by Wiley-lnterscience)). Preferred methods include, but are not limited to, those described below.
  • Scheme 1 illustrates a method for preparing compounds depicted by Formula I.
  • a compound of Formula 1 .1 is heated in the presence of an aqueous acid such as hydrochloric acid to furnish the corresponding pyridinone acid of Formula 1 .2.
  • the intermediate of Formula 1 .2 is subjected to an amide coupling and in situ cyclization reaction with an amino alcohol of Formula 1.3 using a coupling reagent such as HATU [0-(7-azabenzotriazol-1 -y ⁇ )-N,N,N',N -tetramethyluronium hexafluorophosphate].
  • the reaction is carried out in the presence of a suitable base such as
  • Scheme 2 illustrates a method for the preparation of compounds of Formula I.
  • This method commences with reaction of chloroaldehyde 2.1 and an amine of Formula 2.2 using one of many reductive amination protocols known to those skilled in the art.
  • this reaction may be carried out by using a reducing agent such as sodium triacetoxyborohydride in a suitable solvent such as methanol.
  • a reducing agent such as sodium triacetoxyborohydride
  • a suitable solvent such as methanol.
  • the resultant chloroalkylamine 2.3 may be isolated and stored as its HCI salt.
  • the final compound of Formula I may then be prepared by treating a mixture of chloroalkylamine 2.3, acid 1.2, and a base such as diisopropylethylamine with a suitable amide coupling reagent such as BOP-CI [(bis(2-oxo-3-oxazolidinyl)phosphonic chloride], T3P [propylphosphonic anhydride] or HATU (preferably HATU) in a solvent such as dichloromethane.
  • a suitable amide coupling reagent such as BOP-CI [(bis(2-oxo-3-oxazolidinyl)phosphonic chloride], T3P [propylphosphonic anhydride] or HATU (preferably HATU) in a solvent such as dichloromethane.
  • the aminoalcohol coupling partner of Formula 1.3 may be prepared via a wide variety of synthetic methods, which can readily be envisioned and developed by one skilled in the art. These include, but are not limited to, those methods illustrated in Scheme 3.
  • the aminoalcohol of Formula 1.3 may be prepared by carrying out a reductive amination of a ketone of Formula 3.1 with an amine of
  • Another method involves reductive amination of an aldehyde of Formula 3.2 with an amine of Formula 2.2 followed by removal of the TBS protecting group by using a suitable procedure including treatment with methanolic HCI or tetrabutylammonium fluoride.
  • Another method for the synthesis of an aminoalcohol of Formula 1.3 involves alkylation of amine 3.3 with a halide or mesylate of Formula 3.4.
  • Yet another method involves alkylation of an amine of Formula 2.2 with bromoalcohol 3.5.
  • a person skilled in the art may further generalize those syntheses to allow access to a wide variety of amines 2.2 and amino alcohols 1.3 including but not limited to variations in R 2a , R 2b , y, alternative cycloalkyls and heterocycloalkyls A, and variously substituted aryls and heteroaryls R 3 .
  • R 1 -X 4-methylimidazol-1-yl
  • a 3-aminopyridine compound of Formula 4.1 is brominated using /V-bromosuccinimide in a solvent such as a mixture of DMSO and water.
  • the resulting intermediate of Formula 4.2 is then heated with sodium methoxide in a suitable solvent such as 1 ,4-dioxane to afford a compound of Formula 4.3.
  • the intermediate of Formula 4.3 is then treated with a mixture of acetic anhydride and formic acid to afford a formamide of Formula 4.4, which is alkylated with
  • This transformation may be carried out by heating a solution of 4.6 and a base such as triethylamine in an alcohol solvent such as MeOH under an atmosphere of CO in the presence of a suitable palladium catalyst such as Pd(dppf) 2 CI 2 DCM [[1 ,1 '- bis(diphenylphosphino)ferrocene]dichloropalladium(ll), dichloromethane complex].
  • a suitable palladium catalyst such as Pd(dppf) 2 CI 2 DCM [[1 ,1 '- bis(diphenylphosphino)ferrocene]dichloropalladium(ll), dichloromethane complex].
  • Scheme 5 depicts a method for the preparation of compounds of Formula 1.1.
  • a pyridyl derivative of Formula 5.1 is oxidized with an oxidizing agent such as mCPBA [3-chloroperoxybenzoic acid] in a suitable solvent such as dichloroethane to afford the corresponding /V-oxide of Formula 5.2.
  • the intermediate of Formula 5.2 is then heated in the presence of TMSCN [trimethylsilyl cyanide] and a base such as triethylamine in a solvent such as acetonitrile to afford the intermediate of Formula 5.3.
  • TMSCN trimethylsilyl cyanide
  • a base such as triethylamine
  • ester may then be prepared from 5.3 in two steps by subjecting 5.3 to sodium methoxide in a solvent such as THF, followed by treatment with an alcohol and an acid such as HCI.
  • the ester of Formula 5.5 is a versatile intermediate that allows introduction of a variety of heterocycles R 1 X.
  • 5.5 may be subjected to a Suzuki coupling with a heteroarylboronic acid using methods well known to those skilled in the art [see Tetrahedron 2002, 58, 9633-9695].
  • the compound of Formula 5.5 may be coupled to a heterocycle X using a direct arylation approach [see D. Lapointe et al., J. Org. Chem.
  • a suitable palladium catalyst such as allylpalladium chloride dimer and a base such as K 2 CO 3
  • a solvent such as 1 ,4-dioxane
  • the compound of Formula 5.5 may be converted to the
  • boronate 5.6 using a palladium-catalyzed cross coupling with a diboron reagent such as 5,5,5',5'-tetramethyl-2,2'-bi-1 ,3,2-dioxaborinane in the presence of potassium acetate and a palladium catalyst such as Pd(dppf)2Cl2-DCM in a solvent such as 1 ,4-dioxane.
  • a palladium catalyst such as Pd(dppf)2Cl2-DCM in a solvent such as 1 ,4-dioxane.
  • the resulting boronate intermediate of Formula 5.6 can in turn be subjected to a Suzuki coupling with a heteroaryl halide to afford the final compound of Formula 1.1.
  • a heterocycle X involves the use of a Chan-Lam coupling [see Tetrahedron Lett. 2003, 44, 3863-3865, and Synthesis 2008, 5, 795-799].
  • Scheme 6 illustrates a method for the synthesis of compounds of Formula I.
  • the method commences by heating the compound of Formula 6.1 in an acid such as hydrochloric acid to afford pyridinone acid intermediate 6.2.
  • the acid of Formula 6.2 may be subjected to a coupling / cyclization reaction with an aminoalcohol of Formula 1.3 to afford an intermediate of Formula 6.3 using chemistry described in Scheme 1 .
  • the final compound, Formula I may then be formed directly from 6.3 or via boronate 6.4 using the strategies discussed in Scheme 5.
  • compounds of Formula I where heterocycle X is linked to the pyridinone ring via a C-N bond may be formed by nucleophilic aromatic substitution.
  • the method involves heating a mixture of a compound of Formula 1.2, dibromoethane, and a base such as CS2CO3 in a solvent such as DMF to afford lactone intermediate 7.1.
  • the lactone of Formula 7.1 may then be reacted with an amine of Formula 2.2 in the presence of a reagent such as DIBAL (diisobutylaluminum hydride) or bis(trimethylaluminum)-1 ,4-diazabicyclo[2.2.2]octane adduct in a solvent such as THF to afford the amide alcohol of Formula 7.2.
  • a reagent such as DIBAL (diisobutylaluminum hydride) or bis(trimethylaluminum)-1 ,4-diazabicyclo[2.2.2]octane adduct in a solvent such as THF to afford the amide alcohol of Formula 7.2.
  • the ring closure may be carried out in a stepwise fashion by first converting alcohol 7.2 into the corresponding chloride by treatment with thionyl chloride, followed by deprotonation of the amide NH with a suitable base such as lithium
  • Scheme 8 illustrates a method for the synthesis of amines of Formula 8.7, which represent a subset of the general structure of Formula 2.2.
  • the synthesis commences with deprotonation of ethynyl(trimethyl)silane using a suitable base such as n-butyllithium in a solvent such as THF.
  • a suitable base such as n-butyllithium
  • THF a solvent such as THF.
  • This mixture is then added to a solution of an epoxide of Formula 8.1 (see J. Barluenga et al., J. Org. Chem. 1995, 60, 6696- 6699) in a solvent such as THF.
  • This intermediate is then subjected to a cyclization reaction mediated by a platinum catalyst such as di- -chlorodichlorobis(ethylene)diplatinum(ll) and an acid such as trifluoroacetic acid in a solvent such as CH 2 CI 2 to afford a dihydrofuran intermediate of Formula 8.6.
  • Scheme 9 illustrates an alternative method for the synthesis of amines of Formula 8.7, a subset of the general structure of Formula 2.2.
  • the methyl ester of Formula 9.1 is reacted with the dianion resulting from deprotonation of chloroacetic acid (9.2) with a suitable base such as LDA in a solvent such as THF.
  • a- chloroketone of Formula 9.3 is then treated with a suitable reducing agent such as lithium tri-fe/t-butoxyaluminum hydride in a solvent such as diethyl ether to afford chlorohydrin 9.4, which in turn may be converted to the p-nitrobenzoate 9.6 by acylation with p-nitrobenzoyl chloride (9.5) in the presence of DMAP [4-
  • epoxide 9.7 may be subjected to ring opening with the acetylide resulting from deprotonation of 8.2 with a base such as n-butyllithium in the presence of dimethylaluminum chloride in a solvent such as toluene to afford the alkyne of Formula 9.8.
  • This intermediate is then subjected to removal of the trimethylsilyl group by exposure to a protic solvent such as methanol and a base such as potassium carbonate to deliver the deprotected alkyne 9.9.
  • a protic solvent such as methanol and a base such as potassium carbonate
  • This intermediate is then subjected to a Sonogashira coupling with aryl halide 8.4, as described in Scheme 8, to afford the intermediate of Formula 9.10.
  • This intermediate is then subjected to a cyclization reaction mediated by a platinum catalyst such as di- ⁇ - chlorodichlorobis(ethylene)diplatinum(ll), an acid such as p-toluenesulfonic acid, and trimethyl orthoformate in a solvent such as MeOH to afford the compound of Formula 9.11.
  • a platinum catalyst such as di- ⁇ - chlorodichlorobis(ethylene)diplatinum(ll)
  • an acid such as p-toluenesulfonic acid
  • trimethyl orthoformate in
  • suitable acid addition salts include but are not limited to those derived from inorganic acids, such as hydrochloric, hydrobromic, hydrofluoric, hydroiodic, boric, fluoroboric, phosphoric, nitric, carbonic, and sulfuric acids, and organic acids such as acetic, benzenesulfonic, benzoic, ethanesulfonic, fumaric, lactic, maleic, methanesulfonic, trifluoromethanesulfonic, succinic, toluenesulfonic, and trifluoroacetic acids.
  • Suitable organic acids generally include but are not limited to aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic classes of organic acids.
  • suitable organic acids include but are not limited to acetate, trifluoroacetate, formate, propionate, succinate, lactate, maleate, fumarate, benzoate, p-hydroxybenzoate, phenylacetate, mandelate, methanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate, adipate, butyrate, camphorate,
  • suitable salts thereof may be employed for synthesis.
  • Such salts include alkali metal salts, i.e., lithium, sodium or potassium salts; alkaline earth metal salts, e.g., calcium or magnesium salts; and salts formed with suitable organic Iigands such as amines or quaternary ammonium cations.
  • Organic salts of such acidic intermediates may be made from primary, secondary or tertiary amines such as methylamine, diethylamine, ethylenediamine or trimethylamine.
  • Quaternary amines may be prepared by reaction of tertiary amines with agents such as lower alkyl (C-i-C 6 ) halides (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides), dialkyl sulfates (i.e., dimethyl, diethyl, dibutyl, and diamyl sulfates), arylalkyl halides (i.e., benzyl and phenethyl bromides), and others.
  • C-i-C 6 lower alkyl
  • halides e.g., methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides
  • dialkyl sulfates i.e., dimethyl, diethyl, dibutyl, and diamyl sulfates
  • arylalkyl halides i
  • reaction conditions length of reaction and temperature
  • reaction conditions may vary.
  • reactions were followed by thin layer chromatography or mass spectrometry, and subjected to work-up when appropriate.
  • Purifications may vary between experiments: in general, solvents and the solvent ratios used for eluents/gradients were chosen to provide appropriate R f s or retention times.
  • Step 1 Synthesis of methyl 6-methoxy-5-(4-methyl-1 /-/-imidazol-1 -yl)pyridine-2- carboxylate (C2).
  • the reaction was heated to 70 °C under CO atmosphere (3 bar) in a Parr apparatus. After 30 minutes, the pressure dropped to 0.5 bar; additional CO was added until the pressure stayed constant for a period of 30 minutes.
  • the mixture was allowed to cool to room temperature and filtered through a pad of Celite.
  • the Celite pad was washed twice with methanol and the combined filtrates were concentrated under reduced pressure.
  • the residue (88 g) was dissolved in ethyl acetate (1 L) and water (700 mL); the organic layer was washed with water (200 mL), and the aqueous layer was extracted with ethyl acetate (500 mL).
  • the combined organic layers were dried over magnesium sulfate, filtered and concentrated to provide the title compound. Yield: 42.6 g, quantitative.
  • Step 2 Synthesis of 5-(4-methyl-1 H-imidazol-1 -yl)-6-oxo-1 ,6-dihydropyridine-2- carboxylic acid, hydrobromide salt (P1 ).
  • Step 1 Synthesis of 1 -chloro-4-[3-(nnethoxynnethylidene)cyclohexyl]benzene (C5).
  • Step 1 Synthesis of c/s-2-[2-(trifluoromethyl)phenoxy]cyclobutanol (C7).
  • Step 3 Synthesis of 2-( ⁇ frans-2-[2-(thfluoromethyl)phenoxy]cyclobutyl ⁇ amino)ethanol (C9).
  • a mixture of C8 (500 mg, 1 .61 mmol) and 2-aminoethanol (5 mL) was heated at 90 °C for 18 hours, then at 100 °C for an additional 24 hours.
  • the reaction was cooled, diluted with ethyl acetate (100 mL) and washed with aqueous sodium hydroxide solution (1 M, 5 x 50 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo.
  • Step 4 Synthesis of 7-(4-methyl-1 H-imidazol-1 -yl)-2- ⁇ frans-2-[2- (trifluoromethyl)phenoxy]cyclobutyl ⁇ -3,4-dihydro-2H-pyrido[1 ,2-a]pyrazine-1 ,6-dione, trifluoroacetate salt (1 ).
  • Retention time 2.53 minutes (Column: Waters Atlantis dC18, 4.6 x 50 mm, 5 ⁇ ; Mobile phase A: 0.05% trifluoroacetic acid in water (v/v); Mobile phase B: 0.05% trifluoroacetic acid in acetonitrile (v/v); Gradient: 5% to 95% B over 4.0 minutes, linear; Flow rate: 2 mL/minute).
  • Step 1 Synthesis of frans-2-(dibenzylamino)cyclopentanol (C10).
  • Step 2 Synthesis of frans-/V,/ ⁇ /-dibenzyl-2-[2-(trifluoromethyl)phenoxy]cyclopentanamine (C11 ).
  • Step 5 Synthesis of 7-(4-methyl-1 H-imidazol-1 -yl)-2- ⁇ frans-2-[2- (trifluoromethyl)phenoxy]cyclopentyl ⁇ -3,4-dihydro-2/-/-pyrido[1 ,2-a]pyrazine-1 ,6-dione (2).
  • Step 1 Synthesis of 2- ⁇ [c/s-2-(benzyloxy)cyclobutyl]amino ⁇ ethanol (C14).
  • Step 2 Synthesis of 2-[c/ ' s-2-(benzyloxy)cyclobutyl]-7-(4-methyl-1 /-/-imidazol-1 -yl)-3,4- dihydro-2H-pyrido[1 ,2-a]pyrazine-1 ,6-dione (C15).
  • HATU hexafluorophosphate
  • the reaction was stirred at room temperature for 55 hours. Water (200 mL) was added, and the mixture was extracted with dichloromethane (3 x 150 mL). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. Purification via silica gel
  • Step 3 Synthesis of 2-[c/s-2-hydroxycyclobutyl]-7-(4-methyl-1 /-/-imidazol-1 -yl)- 3,4-dihydro-2H-pyrido[1 ,2-a]pyrazine-1 ,6-dione (C16).
  • Step 4 Synthesis of c/ ' s-2-[7-(4-methyl-1 H-imidazol-1 -yl)-1 ,6-dioxo-1 ,3,4,6-tetrahydro- 2H-pyrido[1 ,2-a]pyrazin-2-yl]cyclobutyl methanesulfonate (C17).
  • Methanesulfonyl chloride (148 ⁇ _, 1 .91 mmol) was added drop-wise to a 0 °C solution of C16 (150 mg, 0.47 mmol) and triethylamine (530 ⁇ _, 3.82 mmol) in
  • Step 5 Synthesis of 2- ⁇ frans-2-[(6,7-difluoronaphthalen-1 -yl)oxy]cyclobutyl ⁇ -7-(4-methyl- 1 H-imidazol-1 -yl)-3,4-dihydro-2/-/-pyrido[1 ,2-a]pyrazine-1 ,6-dione (3).
  • Retention time 2.58 minutes (Column: Waters Atlantis dC18, 4.6 x 50 mm, 5 ⁇ ; Mobile phase A: 0.05% trifluoroacetic acid in water (v/v); Mobile phase B: 0.05% trifluoroacetic acid in acetonitrile (v/v); Gradient: 5% to 95% B over 4.0 minutes, linear; Flow rate: 2 mL/minute).
  • Example 4
  • Step 1 Synthesis of 7-(4-methyl-1 /-/-imidazol-1 -yl)-2-(prop-2-en-1 -yl)-3,4-dihydro-2H- pyhdo[1 ,2-a]pyrazine-1 ,6-dione (C18).
  • HATU 0-(7-Azabenzotriazol-1 -yl)-/V,/V,/V',/ ⁇ / - tetramethyluronium hexafluorophosphate
  • Step 2 Synthesis of (E)-1 -[4-chloro-3-(thfluoromethyl)phenyl]-/V-hydroxymethanimine (C19).
  • Step 3 Synthesis of 4-chloro-/V-hydroxy-3-(trifluoromethyl)benzenecarboximidoyl chloride (C20).
  • Step 4 Synthesis of 2-( ⁇ 3-[4-chloro-3-(trifluoromethyl)phenyl]-4,5-dihydro-1 ,2-oxazol-5- yl ⁇ methyl)-7-(4-methyl-1 H-imidazol-1 -yl)-3,4-dihydro-2/-/-pyrido[1 ,2-a]pyrazine-1 ,6-dione (4).
  • Step 1 Synthesis of frans-2-[(2-hydroxyethyl)amino]cyclopentanol (C21 ).
  • Step 3 Synthesis of 2- ⁇ c/s-2-[4-fluoro-2-(trifluoromethyl)phenoxy]cyclopentyl ⁇ -7-(4- methyl-1 H-imidazol-1 -yl)-3,4-dihydro-2H-pyrido[1 ,2-a]pyrazine-1 ,6-dione (5).
  • Triphenylphosphine (12.2 mg, 0.046 mmol) was added to a solution of C22 (1 1 mg, 0.033 mmol) and 4-fluoro-2-(trifluoromethyl)phenol (7.4 mg, 0.041 mmol) in tetrahydrofuran (0.5 mL).
  • the reaction mixture was treated with a solution of diisopropyl azodicarboxylate (94%, 0.015 mL, 0.071 mmol) in tetrahydrofuran, and heated at 50 °C for 18 hours, then at 90 °C for 4 hours.
  • Retention time 2.32 minutes (Column: Waters Atlantis dC18, 4.6 x 50 mm, 5 ⁇ ; Mobile phase A: 0.05% trifluoroacetic acid in water (v/v); Mobile phase B: 0.05% trifluoroacetic acid in acetonitrile (v/v); Gradient: 5% to 95% B over 4.0 minutes, linear; Flow rate: 2 mL/minute).
  • Example 6
  • Step 1 Synthesis of (5S)-5-( ⁇ [fe/t-butyl(diphenyl)silyl]oxy ⁇ methyl)furan-2(5H)-one (C23).
  • Step 4 Synthesis of terf-butyl( ⁇ (2S,3S,5R)-3-methyl-5-[4- (trifluoromethyl)phenyl]tetrahydrofuran-2-yl ⁇ methoxy)diphenylsilane (C26).
  • Tetrabutylammonium fluoride (1 .0 M solution in tetrahydrofuran, 2.62 ml_, 2.62 mmol) was added to a solution of C26 (1 .19 g, 2.39 mmol) in tetrahydrofuran (15 ml_). After 1 hour at room temperature, te/t-butyl methyl ether was added, and the mixture was washed with water, dried over sodium sulfate, filtered, and concentrated in vacuo. Chromatography on silica gel (Gradient: 10% to 50% ethyl acetate in heptane) provided the product as a colorless oil. Yield: 530 mg, 2.04 mmol, 85%.
  • Step 8 Synthesis of 7-(4-methyl-1 H-imidazol-1 -yl)-2-( ⁇ (2S,3S,5R)-3-methyl-5-[4- (trifluoromethyl)phenyl]tetrahydrofuran-2-yl ⁇ methyl)-3,4-dihydro-2/-/-pyrido[1 ,2- a]pyrazine-1 ,6-dione (6).
  • Step 1 Synthesis of (5S)-5-( ⁇ [ieri-butyl(diphenyl)silyl]oxy ⁇ nnethyl)dihydrofuran-2(3/-/)- one (C30).
  • the product was prepared from C32 using the general procedure for synthesis of C26 in Example 6. In this case, purification was carried out using silica gel
  • the product obtained as a thick oil that slowly solidified, was prepared from C33 according to the general procedure for the synthesis of C27 in Example 6. Yield: 392 mg, 1 .48 mmol, 84%. The indicated relative stereochemistry was consistent with NOE studies carried out on this sample.
  • Step 1 Synthesis of (2S,3S)-2-(dibenzylamino)hex-5-yn-3-ol (C38).
  • Step 3 Synthesis of (1 S)-/V,/V-dibenzyl-1 - ⁇ (2S)-5-[4-(thfluoromethyl)phenyl]-2,3- dihydrofuran-2-yl ⁇ ethanamine (C40).
  • Trifluoroacetic acid (18 mL, 230 mmol) and di- ⁇ - chlorodichlorobis(ethylene)diplatinum(ll) (97%, 3.76 g, 6.20 mmol) were added to a solution of C39 (49.4 g, 1 13 mmol) in dichloromethane (80 mL). After 1 .5 hours at room temperature, the reaction mixture was poured into aqueous sodium hydroxide solution (0.5 M, 500 mL), and the aqueous layer was extracted with dichloromethane (250 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo.
  • Step 4 Synthesis of (1 S)-1 - ⁇ (2S,5R)-5-[4-(trifluoromethyl)phenyl]tetrahydrofuran-2- yljethanamine (C41 ).
  • Step 5 Synthesis of 1 -(2-hydroxyethyl)-5-(4-methyl-1 /-/-imidazol-1 -yl)-6-oxo-/V-[(1 S)-1 - ⁇ (2S,5R)-5-[4-(trifluoromethyl)phenyl]tetrahydrofuran-2-yl ⁇ ethyl]-1 ,6-dihydropyridine-2- carboxamide (C42).
  • Step 6 Synthesis of 7-(4-methyl-1 H-imidazol-1 -yl)-2-[(1 S)-1 - ⁇ (2S,5R)-5-[4- (trifluoromethyl)phenyl]tetrahydrofuran-2-yl ⁇ ethyl]-3,4-dihydro-2/-/-pyrido[1 ,2-a]pyrazine- 1 ,6-dione (8).
  • reaction mixture was stirred at room temperature for 40 minutes, then cooled again in an ice bath, treated with 1 ,3,4,6,7,8-hexahydro-2/-/-pyrimido[1 ,2-a]pyrimidine (97%, 30.2 g, 210 mmol), and stirred for 2.5 hours.
  • Ethyl acetate (500 mL) was added to the cold reaction mixture, which was subsequently washed with water (2 x 500 mL).
  • the aqueous layer was extracted with ethyl acetate (500 mL) and the combined organic layers were washed with saturated aqueous sodium chloride solution (250 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo.
  • Step 1 Synthesis of terf-butyl [(2S)-4-chloro-3-oxobutan-2-yl]carbamate (C43).
  • a solution of chloroacetic acid (23.2 g, 246 mmol) in tetrahydrofuran (100 mL) was added over 35 minutes to a -78 °C solution of lithium diisopropylamide in tetrahydrofuran (2.05 M, 240 mL, 492 mmol), at a rate that kept the internal temperature below -65 °C.
  • reaction mixture was quickly transferred into a (dry ice)-jacketed addition funnel and added over 5 minutes to a solution of methyl N-(tert- butoxycarbonyl)-L-alaninate (10.0 g, 49.2 mmol) in tetrahydrofuran (120 mL).
  • the resulting solid was isolated via filtration and washed with methylcyclohexane to provide the product (3.1 g).
  • the filtrate was concentrated, mixed with pentane (25 mL), heated to reflux, cooled with stirring and seeded with solid product.
  • the resulting material was filtered and rinsed with pentane to provide the product as a solid (8.1 g). Total yield: 1 1 .2 g, 50.1 mmol, 69%.
  • a 0.1 M potassium phosphate buffer, 2.0 mM in magnesium chloride, was prepared by combining potassium dihydrogenphosphate (9.86 g, 72.4 mmol), potassium hydrogenphosphate (22.2 g, 127 mmol) and magnesium chloride hexahydrate (0.812 g, 4.0 mmol) in water (2 L); the pH of the resulting solution was 7.05.
  • phosphate buffer (1 .8 L) was added nicotinamide adenine dinucleotide phosphate, disodium salt trihydrate (1 .9 g, 2.4 mmol) and ketoreductase enzyme (Codexis, KRED-P1 -E05) (8 g), and the mixture was stirred for 45 minutes at 22 °C to dissolve the ketoreductase.
  • ketoreductase enzyme Codexis, KRED-P1 -E05
  • the resulting emulsion was filtered through diatomaceous earth (200 g), and the filter cake was broken and washed with te/t-butyl methyl ether (3 x 400 ml_).
  • the combined organic layers from the filtrates were dried with sodium sulfate (625 g), filtered, and concentrated in vacuo to afford the crude product as a red oil (50 g).
  • This material was mixed with ethyl acetate (80 ml_) and treated with decolorizing carbon (5 g) over 10 minutes with gentle heating. After filtration through Celite, the solution was concentrated in vacuo and mixed with warm hexanes (40 ml_) under stirring.
  • Step 3 Synthesis of (2R,3S)-3-[(terf-butoxycarbonyl)amino]-1 -chlorobutan-2-yl 4- nitrobenzoate (C45).
  • a solution of C44 (15 g, 67 mmol) in dichloromethane (400 mL) was cooled to 0 °C and treated with triethylamine (1 1 .7 mL, 83.9 mmol) and 4-(dimethylamino)pyridine (99%, 827 mg, 6.70 mmol).
  • a solution of 4-nitrobenzoyl chloride (15.6 g, 84.1 mmol) in dichloromethane (100 mL) was then added, and the reaction mixture was allowed to slowly warm to room temperature over 18 hours.
  • n-Butyllithium (2.5 M solution in hexanes, 39.7 mL, 99 mmol) was added drop- wise to a -20 °C solution of ethynyl(trimethyl)silane (15 mL, 1 10 mmol) in toluene (100 mL), at a rate that kept the reaction temperature below -15 °C.
  • the reaction mixture was stirred for 15 minutes at this temperature.
  • Dimethylaluminum chloride (97%, 1 .0 M solution in hexanes, 96 mL, 96 mmol) was added, and the reaction flask was immersed in an ice bath for 1 hour, then warmed to room temperature for 30 minutes.
  • Step 7 Synthesis of terf-butyl ⁇ (2S,3S)-6-[4-chloro-2-(trifluoromethyl)phenyl]-3- hydroxyhex-5-yn-2-yl ⁇ carbamate (C49).
  • Step 8 Synthesis of ferf-butyl [(1 S)-1 - ⁇ (2S)-5-[4-chloro-2-(trifluoromethyl)phenyl]-5- methoxytetrahydrofuran-2-yl ⁇ ethyl]carbamate (C50).
  • reaction mixture was poured into saturated aqueous sodium bicarbonate solution (400 mL) and extracted with terf-butyl methyl ether; the combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo to afford the product as a thick oil, which was taken directly to the following reaction.
  • Step 9 Synthesis of terf-butyl [(1 S)-1 - ⁇ (2S,5R)-5-[4-chloro-2- (trifluoromethyl)phenyl]tetrahydrofuran-2-yl ⁇ ethyl]carbamate (C51 ).
  • Trifluoroacetic acid 25 mL, 340 mmol was added to a solution of C51 (16.4 g, 41 .6 mmol) in dichloromethane (250 mL). The reaction mixture was stirred at room temperature for 18 hours, then poured into aqueous sodium hydroxide solution (1 M, 350 mL). Additional dichloromethane (500 mL) was added, and the aqueous layer was extracted with dichloromethane (2 x 200 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to provide the product as a brown oil. Yield: 12 g, 41 mmol, 98%.
  • Step 1 1 . Synthesis of A/-[(1 S)-1 - ⁇ (2S,5R)-5-[4-chloro-2-
  • Step 1 Synthesis of (2S,3S)-2-(dibenzylamino)-6-[3,5-difluoro-4- (trifluoromethyl)phenyl]hex-5-yn-3-ol (C54).
  • Step 3 Synthesis of (1 S)-1 - ⁇ (2S,5R)-5-[3,5-difluoro-4- (trifluoromethyl)phenyl]tetrahydrofuran-2-yl ⁇ ethanamine (C56).
  • the product was prepared from C55 according to the general procedure for the synthesis of C41 in Example 8, except that te/t-butyl methyl ether was used in the work- up rather than ethyl acetate.
  • the product was obtained as an oil. Yield: 629 mg, 2.10 mmol, 90%.
  • Step 4 Synthesis of A/-[(1 S)-1 - ⁇ (2S,5R)-5-[3,5-difluoro-4- (thfluoromethyl)phenyl]tetrahydrofuran-2-yl ⁇ ethyl]-1 -(2-hydroxyethyl)-5-(4-methyl-1 H- imidazol-1 -yl)-6-oxo-1 ,6-dihydropyridine-2-carboxamide (C57).
  • Step 5 Synthesis of 1 -(2-chloroethyl)-/V-[(1 S)-1 - ⁇ (2S,5R)-5-[3,5-difluoro-4- (thfluoromethyl)phenyl]tetrahydrofuran-2-yl ⁇ ethyl]-5-(4-methyl-1 /-/-imidazol-1 -yl)-6-oxo- 1 ,6-dihydropyridine-2-carboxannide (C58).
  • Lithium bis(trimethylsilyl)amide (1 M solution in THF, 2.24 mL, 2.24 mmol) was added drop-wise to a 0 °C solution of C58 (from the preceding step, 1 .00 g, 1 .79 mmol) in tetrahydrofuran (20 mL), and the reaction mixture was stirred at 0 °C for 15 minutes. The ice bath was removed, and stirring was continued for 1 hour. After cooling to 0 °C, the reaction was quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo.
  • Step 1 Synthesis of 2-[4-(trifluoromethyl)phenyl]hex-5-en-2-ol (C59).
  • Step 3 Synthesis of ⁇ c/s-5-methyl-5-[4-(trifluoromethyl)phenyl]tetrahydrofuran-2- yljmethyl 4-methylbenzenesulfonate (C61 ).
  • Step 1 Synthesis of methyl 5-[4-(trifluoromethyl)phenyl]furan-2-carboxylate (C64).
  • Lithium aluminum hydride (2 M solution in tetrahydrofuran, 0.26 ml_, 0.52 mmol) was added to a solution of C66 (125 mg, 0.434 mmol) in diethyl ether (2 ml_), and the reaction mixture was stirred at room temperature for 1 hour. After acidification with aqueous hydrochloric acid, the mixture was extracted with ethyl acetate, and the combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo to afford the product as an oil, presumed to be a ⁇ 1 :1 mixture of
  • the product was prepared from C68 using the general method described for synthesis of C9 in Example 1 . In this case, the product was used in the next step without HPLC purification. Yield: 295 mg, 0.973 mmol, 94%.
  • Step 7 Synthesis of 7-(4-methyl-1 H-imidazol-1 -yl)-2-( ⁇ c/s-2-methyl-5-[4- (trifluoromethyl)phenyl]tetrahydrofuran-2-yl ⁇ methyl)-3,4-dihydro-2/-/-pyrido[1 ,2- a]pyrazine-1 ,6-dione, formate salt (13) and 7-(4-methyl-1 H-imidazol-1 -yl)-2-( ⁇ frans-2- methyl-5-[4-(trifluoromethyl)phe
  • Example 13 was the first-eluting isomer, isolated as a glass. Yield: 38 mg, 71 ⁇ , 7%.
  • Step 1 Synthesis of 1 -[4-(trifluoromethyl)phenyl]hex-5-en-1 -ol (C70).
  • N- iodosuccinimide 95%, 5.0 g, 21 mmol
  • the reaction mixture was stirred at room temperature for 18 hours.
  • the mixture was extracted with ethyl acetate (3 x 15 mL), and the combined organic layers were washed with saturated aqueous sodium chloride solution (15 mL), dried over sodium sulfate, filtered, and concentrated in vacuo.
  • Purification via silica gel chromatography (Gradient: 1 % to 10% ethyl acetate in petroleum ether) provided the product as a yellow oil.
  • Step 4 Synthesis of 7-(4-methyl-1 /-/-imidazol-1 -yl)-2-( ⁇ frans-6-[4- (trifluoromethyl)phenyl]tetrahydro-2/-/-pyran-2-yl ⁇ methyl)-3,4-dihydro-2/-/-pyrido[1 ,2- a]pyrazine-1 ,6-dione, formate salt (15) and 7-(4-methyl-1 /-/-imidazol-1 -yl)-2-( ⁇ c/s-6-[4- (trifluoromethyl)phenyl]tetrahydro-2/-/-pyran-2-yl ⁇ methyl)-3,4-dihydro-2/-/-pyrido[1 ,2- a]pyrazine-1 ,6-dione, formate salt (16).
  • Example 16 came off the column before Example 15; both were obtained as white solids. The indicated relative stereochemistry was assigned on the basis of NOE studies.
  • Example 15 Yield, 4.7 mg, 8.8 ⁇ , 1 .3%.
  • Example 16 32.8 mg, 61 .6 ⁇ , 9%.
  • 1 H NMR 400 MHz, CD 3 OD
  • Step 1 Synthesis of (3S,5S)-5-( ⁇ [terf-butyl(diphenyl)silyl]oxy ⁇ methyl)-3- methyldihydrofuran-2(3H)-one (C73).
  • a solution of C30 (1 .02 g, 2.88 mmol) in tetrahydrofuran (15 mL) was added drop-wise to a -78 °C solution of lithium bis(trimethylsilyl)amide (1 .0 M in heptane, 3.45 mL, 3.45 mmol) in tetrahydrofuran (12 mL); after 30 minutes, iodomethane (0.215 mL, 3.45 mmol) was added to the cold solution, which was then stirred at -78 °C for 30 minutes, warmed to -50 °C and stirred at that temperature for 3 hours.
  • Step 3 Synthesis of terf-butyl( ⁇ (2S,4S,5R)-4-methyl-5-[4- (trifluoromethyl)phenyl]tetrahydrofuran-2-yl ⁇ methoxy)diphenylsilane (C75).
  • Compound C74 ( ⁇ 1 .51 mmol) was converted to the product, obtained as an oil, using the method described for synthesis of C26 in Example 6. Yield: 336 mg, 0.674 mmol, 45% over 2 steps.
  • Step 7 Synthesis of 7-(4-methyl-1 H-imidazol-1 -yl)-2-( ⁇ (2S,4S,5R)-4-methyl-5-[4- (trifluoromethyl)phenyl]tetrahydrofuran-2-yl ⁇ methyl)-3,4-dihydro-2/-/-pyndo[1 ,2- a]pyrazine-1 ,6-dione, trifluoroacetate salt (17).
  • Step 2 Synthesis of A/-(2-hydroxyethyl)-/V-[(2S)-2-hydroxy-5-(trimethylsilyl)pent-4-yn-1 - yl]-5-(4-methyl-1 H-imidazol-1 -yl)-6-oxo-1 ,6-dihydropyridine-2-carboxamide (C80).
  • Step 3 Synthesis of 2-[(2S)-2-hydroxy-5-(thmethylsilyl)pent-4-yn-1 -yl]-7-(4-methyl-1 H- imidazol-1 -yl)-3,4-dihydro-2/-/-pyrido[1 ,2-a]pyrazine-1 ,6-dione (C81 ).
  • Step 4 Synthesis of 2-[(2S)-2-hydroxypent-4-yn-1 -yl]-7-(4-methyl-1 H-imidazol-1 -yl)-3,4- dihydro-2H-pyrido[1 ,2-a]pyrazine-1 ,6-dione (C82).
  • Step 5 Synthesis of 2- ⁇ (2S)-5-[3,5-difluoro-4-(trifluoromethyl)phenyl]-2-hydroxypent-4- yn-1 -yl ⁇ -7-(4-methyl-1 H-imidazol-1 -yl)-3,4-dihydro-2/-/-pyrido[1 ,2-a]pyrazine-1 ,6-dione (C83).
  • Step 6 Synthesis of 2-( ⁇ (2S,5R)-5-[3,5-difluoro-4- (thfluoromethyl)phenyl]tetrahydrofuran-2-yl ⁇ methyl)-7-(4-nnethyl-1 /-/-imidazol-1 -yl)-3,4- dihydro-2H-pyrido[1 ,2-a]pyrazine-1 ,6-dione (18).
  • Step 1 Synthesis of /V-substituted 2- ⁇ [te/t-butyl(dimethyl)silyl]oxy ⁇ ethanamine C84.
  • Step 3 Synthesis of 2-substituted 7-(4-methyl-1 /-/-imidazol-1 -yl)-3,4-dihydro-2H- pyrido[1 ,2-a]pyrazine-1 ,6-dione M1 .
  • HATU W,W,W,W-tetramethyluronium hexafluorophosphate
  • terf-Butyl (frans-3-hydroxycyclobutyl)carbamate (P. Liu, PCT Int. Appl. 2007, WO 2007062332 A2) was treated with carbon tetrabromide and triphenylphosphine to produce te/t-butyl (c/s-3-bromocyclobutyl)carbamate, which was subjected to reaction with 2-(trifluoromethyl)phenol, then deprotected with acid to yield trans-3-[2- (trifluoromethyl)phenoxy]cyclobutanamine. This was converted to the requisite 2- aminoethanol using the general method described in Method A.
  • the requisite amine may be prepared according to T. A. Shepherd et al., J. Med. Chem. 2002, 45, 2101 -21 1 1 .
  • Cyclobutanecarbonitrile was alkylated with 1 -(bromomethyl)-4-fluorobenzene, and the product was reduced with lithium aluminum hydride to generate 1 -[1 -(4- fluorobenzyl)cyclobutyl]methanamine.
  • Example 46 and exhibited an IC 50 of 51 1 nM.
  • Example 46 was assigned on the basis of its lower IC50 (see Table 1 ), in analogy to the other compounds described herein.
  • Example 47 was isolated from the racemic mixture via supercritical fluid chromatography (Column: Chiralcel OJ-H, 5 ⁇ ; Eluent: 65:35 carbon dioxide / propanol containing 0.2% isopropylamine), and was the second of the enantiomers that eluted from the column.
  • the first-eluting material was the enantiomer of
  • Example 47 and exhibited an IC50 of 329 nM.
  • the absolute stereochemistry of Example 47 was assigned on the basis of its lower IC50 (see Table 1 ), in analogy to the other compounds described herein.
  • Example 48 was isolated from the racemic mixture via supercritical fluid chromatography (Column: Chiralcel OJ-H, 5 ⁇ ; Eluent: 3:1 carbon dioxide / methanol containing 0.2% isopropylamine), and was the second of the enantiomers that eluted from the column.
  • the first-eluting material was the enantiomer of
  • Example 48 and exhibited an IC 50 of 1230 nM.
  • the absolute stereochemistry of Example 48 was assigned on the basis of its lower IC 50 (see Table 1 ), in analogy to the other compounds described herein.
  • This alkyne was prepared via reaction of terf-butyl[(2S)-oxiran-2-ylmethoxy]diphenylsilane with 4- chloro-1 -ethynyl-2-methoxybenzene, using n-butyllithium and boron trifluoride diethyl etherate.
  • the final ring closure was carried out via a Mitsunobu reaction using diisopropyl azodicarboxylate.
  • Example 58 was isolated from the racemic mixture via supercritical fluid chromatography (Column: Chiralcel OJ-H, 5 ⁇ ; Eluent: 4:1 carbon dioxide / methanol containing 0.2% isopropylamine), and was the second of the enantiomers that eluted from the column.
  • the first-eluting material was the enantiomer of
  • Example 58 and exhibited an IC50 of 1040 nM.
  • Example 58 was assigned on the basis of its lower IC50 (see Table 1 ), in analogy to the other compounds described herein. 33. 1 -Chloro-2-fluoro-4-iodo-5-methoxybenzene was used as starting material; see J. M. Blaney et al., PCT Int. Appi, 2008150914, Dec 1 1 , 2008.
  • Example 62 was isolated from the racemic mixture via HPLC (Column:
  • Example 62 Phenomenex Lux Cellulose-3, 5 ⁇ ; Gradient: 50% to 100% ethanol in heptane), and was the second of the enantiomers that eluted from the column.
  • the first- eluting material was the enantiomer of Example 62, and exhibited an IC50 of 723 nM.
  • the absolute stereochemistry of Example 62 was assigned on the basis of its lower IC 50 (see Table 1 ), in analogy to the other compounds described herein.
  • reaction was carried out with di- ⁇ - chlorodichlorobis(ethylene)diplatinum(ll) and water, to yield intermediate terf-butyl [(1 S)-1 - ⁇ (2S)-5-[4-chloro-2-(difluoromethoxy)phenyl]-5-hydroxytetrahydrofuran-2- yl ⁇ ethyl]carbamate.
  • Example 66 was a minor diastereomer isolated during purification of Example 17, and was presumed to have the stereochemistry shown.
  • the requisite aryl starting material was prepared from the appropriate fluorinated aniline via halogenation with an /V-halosuccinimide, followed by Sandmeyer reaction.
  • amyloid beta protein ⁇ (1 - 42) was determined using human WT-APP overexpressing CHO cells. Cells were plated at 22,000 cells/100 ⁇ _ well in 96 well tissue culture treated, clear plates (Falcon) in DMEM/F12 based medium and incubated for 24 hours at 37 °C.
  • Coating of ELISA assay plates was initiated by addition of 50 L/well of an in- house ⁇ (1 -42) specific antibody at (3 pg/mL) in 0.1 M NaHCO 3 (pH 9.0) into black 384-well Maxisorp ® plates (Nunc) and incubated overnight at 4 °C.
  • the capture antibody was then aspirated from the ELISA assay plates and plates were washed via (2 x 100 ⁇ to 4 x 100 ⁇ ) washes with Wash Buffer (Dulbecco's PBS, 0.05% Tween 20).
  • 90 pL/well of Blocking Buffer (Dulbecco's PBS, 1 .0% BSA (Sigma A7030)) was then added to plates.

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Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015049616A1 (en) * 2013-10-04 2015-04-09 Pfizer Inc. Novel bicyclic pyridinones as gamma-secretase modulators
WO2016125048A1 (en) * 2015-02-03 2016-08-11 Pfizer Inc. Novel cyclopropabenzofuranyl pyridopyrazinediones
JP2017512803A (ja) * 2014-04-01 2017-05-25 ファイザー・インク ガンマセクレターゼモジュレーターとしてのクロメンおよび１，１ａ，２，７Ｂ−テトラヒドロシクロプロパ［Ｃ］クロメンピリドピラジンジオン
US9802927B2 (en) 2015-06-10 2017-10-31 Denali Therapeutics, Inc. Oxadiazine compounds and methods of use thereof
WO2017216279A1 (en) 2016-06-16 2017-12-21 F. Hoffmann-La Roche Ag Heteroaryl estrogen receptor modulators and uses thereof
US10112943B2 (en) 2012-12-20 2018-10-30 Janssen Pharmaceutica Nv Substituted imidazoles as gamma secretase modulators
US10246454B2 (en) 2013-01-17 2019-04-02 Janssen Pharmaceutica Nv Substituted 3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-diones as gamma secretase modulators
US10562897B2 (en) 2014-01-16 2020-02-18 Janssen Pharmaceutica Nv Substituted 3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-diones as gamma secretase modulators
WO2020072601A1 (en) 2018-10-02 2020-04-09 Frequency Therapeutics, Inc. Pharmaceutical compositions comprising otic therapeutic agents and related methods
WO2020210388A1 (en) 2019-04-08 2020-10-15 Frequency Therapeutics, Inc. Combination of chir99021 and valproic acid for treating hearing loss
US10925872B2 (en) 2016-12-16 2021-02-23 Pipeline Therapeutics, Inc. Methods of treating cochlear synaptopathy
US11827627B2 (en) 2021-06-04 2023-11-28 Vertex Pharmaceuticals Incorporated N-(hydroxyalkyl (hetero)aryl) tetrahydrofuran carboxamides as modulators of sodium channels
US11834441B2 (en) 2019-12-06 2023-12-05 Vertex Pharmaceuticals Incorporated Substituted tetrahydrofurans as modulators of sodium channels

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
UA110688C2 (uk) 2012-09-21 2016-01-25 Пфайзер Інк. Біциклічні піридинони
CN113402490B (zh) * 2021-03-29 2023-01-03 白银京宇新药业有限公司 一种1，2，6，7-四氢-8H-茚并[5，4-b]呋喃-8-酮的制备方法
CN114034792B (zh) * 2021-11-09 2024-06-25 山东新华制药股份有限公司 检测氯酮含量的液相色谱分析方法

Citations (52)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5750349A (en) 1993-01-25 1998-05-12 Takeda Chemical Industries Ltd. Antibodies to β-amyloids or their derivatives and use thereof
EP0994728A1 (en) 1997-04-09 2000-04-26 Mindset, Ltd. Recombinant antibodies specific for beta-amyloid ends, dna encoding and methods of use thereof
US6174884B1 (en) 1997-03-11 2001-01-16 Bayer Aktiengesellschaft 1,5-dihydro-pyrazolo[34-D]-pyrimidinone derivatives
US6235742B1 (en) 1997-10-24 2001-05-22 Pfizer Inc. 5-substituted pyrazolo[4,3-D]pyrimidin-7-ones
WO2002020521A1 (de) 2000-09-11 2002-03-14 Merck Patent Gmbh Verwendung von indolderivaten zur behandlung von erkrankungen des zentralen nervensystems
EP1257584A2 (en) 2000-02-24 2002-11-20 Washington University St. Louis Humanized antibodies that sequester amyloid beta peptide
US20030073655A1 (en) 1997-04-09 2003-04-17 Chain Daniel G. Specific antibodies to amyloid beta peptide, pharmaceutical compositions and methods of use thereof
US20030195205A1 (en) 2001-11-02 2003-10-16 Pfizer Inc. PDE9 inhibitors for treating cardiovascular disorders
WO2004032868A2 (en) 2002-10-09 2004-04-22 Rinat Neuroscience Corp. Methods of treating alzheimer's disease using antibodies directed against amyloid beta peptide and compositions thereof
US20040192898A1 (en) 2001-08-17 2004-09-30 Jia Audrey Yunhua Anti-abeta antibodies
US20040220186A1 (en) 2003-04-30 2004-11-04 Pfizer Inc. PDE9 inhibitors for treating type 2 diabetes,metabolic syndrome, and cardiovascular disease
US20050019328A1 (en) 1997-12-02 2005-01-27 Neuralab Limited Prevention and treatment of amyloidogenic disease
US20050043354A1 (en) 2003-06-19 2005-02-24 Pfizer Inc NK1 antagonist
US20050048049A1 (en) 1997-12-02 2005-03-03 Neuralab Limited Prevention and treatment of amyloidogenic disease
WO2005025616A1 (ja) 2003-09-09 2005-03-24 Takeda Pharmaceutical Company Limited 抗体の用途
WO2005049616A1 (en) 2003-11-24 2005-06-02 Pfizer Limited 5,7-DIAMINOPYRAZOLO [4,3-d] PYRIMIDINES WITH PDE-5 INHIBITING ACTIVITY
US20050256135A1 (en) 2004-05-12 2005-11-17 Graham Lunn Tetrahydronaphthyridine derivatives
US20050267095A1 (en) 2004-05-07 2005-12-01 Patrick Bernardelli 3- or 4-monosubstituted phenol and thiophenol derivatives useful as H3 ligands
WO2006036291A2 (en) 2004-07-30 2006-04-06 Rinat Neuroscience Corp. Antibodies directed against amyloid-beta peptide and methods using same
WO2006043006A1 (fr) 2004-10-21 2006-04-27 Commissariat A L'energie Atomique Revetement nanostructure et procede de revetement
US20060106035A1 (en) 2002-08-23 2006-05-18 Martin Hendrix Phenyl-substituted pyrazolopyrimidines
US20060111372A1 (en) 2002-08-23 2006-05-25 Bayer Healthcare Ag Alkyl-substituted pyrazolopyrimidines
WO2006069081A2 (en) 2004-12-22 2006-06-29 Washington University In St. Louis USE OF ANTI-Aβ ANTIBODY TO TREAT TRAUMATIC BRAIN INJURY
US7115600B2 (en) 2004-02-02 2006-10-03 Pfizer Inc. Histamine-3 receptor modulators
WO2006118959A2 (en) 2005-04-29 2006-11-09 Rinat Neuroscience Corp. Antibodies directed against amyloid-beta peptide and methods using same
WO2006120552A2 (en) 2005-05-12 2006-11-16 Pfizer Inc. ANHYDROUS CRYSTALLINE FORMS OF N-[1-(2-ETHOXYETHYL)-5-(N-ETHYL-N-METHYLAMINO)-7-(4-METHYLPYRIDIN-2-yl-AMINO)-1H-PYRAZOLO[4,3-d]PYRIMIDINE-3-CARBONYL]METHANESULFONAMIDE
WO2006126083A1 (en) 2005-05-24 2006-11-30 Pharmacia & Upjohn Company Llc Pyridine [3 , 4-b] pyrazinone compounds as pde-5 inhibitors
WO2006126081A2 (en) 2005-05-24 2006-11-30 Pharmacia & Upjohn Company Llc Pyridino [2 , 3-b] pyrazinones as pde-5 inhibitors
WO2006126082A2 (en) 2005-05-24 2006-11-30 Pharmacia & Upjohn Company Llc Pyridine [3,4-b] pyrazinones as pde-5 inhibitors
WO2006136924A1 (en) 2005-06-22 2006-12-28 Pfizer Products Inc. Histamine-3 receptor antagonists
US20070060534A1 (en) 2005-06-30 2007-03-15 Threshold Pharmaceuticals, Inc. Anthracycline analogs
WO2007062332A2 (en) 2005-11-18 2007-05-31 Glaxo Group Limited Novel intermediates and their use
WO2007063385A2 (en) 2005-12-01 2007-06-07 Pfizer Products Inc. Spirocyclic amine histamine-3 receptor antagonists
WO2007069053A1 (en) 2005-12-14 2007-06-21 Pfizer Products Inc. Benzimidazole antagonists of the h-3 receptor
US20070179175A1 (en) 2005-11-04 2007-08-02 Graham Lunn Tetrahydronaphthyridine Derivative
WO2007088450A2 (en) 2006-02-01 2007-08-09 Pfizer Products Inc. Chromane antagonist of the h-3 receptor
WO2007088462A1 (en) 2006-02-01 2007-08-09 Pfizer Products Inc. Spirochromane antagonists of the h-3 receptor
WO2007099423A1 (en) 2006-03-02 2007-09-07 Pfizer Products Inc. 1-pyrrolidine indane derivatives as histamine-3 receptor antagonists
WO2007105053A2 (en) 2006-03-13 2007-09-20 Pfizer Products Inc. Tetralines antagonists of the h-3 receptor
US7285293B2 (en) 2000-11-03 2007-10-23 Gerardo Castillo Methods of isolating amyloid-inhibiting compounds and use of compounds isolated from Uncaria tomentosa and related plants
WO2007122466A1 (en) 2006-04-21 2007-11-01 Pfizer Products Inc. Pyridine[3,4-b]pyrazinones
US20070265332A1 (en) 2006-05-15 2007-11-15 Min Ge Antidiabetic bicyclic compounds
WO2007138431A2 (en) 2006-05-30 2007-12-06 Pfizer Products Inc. Azabicyclic ether histamine-3 antagonists
US20080096955A1 (en) 2005-10-27 2008-04-24 Pfizer Inc Histamine-3 receptor antagonists
US20080176925A1 (en) 2007-01-22 2008-07-24 Pfizer Inc Toluene sulfonic acid salt of a therapeutic compound and pharmaceutical compositions thereof
WO2008150914A1 (en) 2007-05-29 2008-12-11 Sgx Pharmaceuticals, Inc. Substituted pyrrolopyridines and pyrazolopyridines as kinase modulators
US20090062529A1 (en) 2007-08-31 2009-03-05 Teiji Kimura Multi-cyclic compounds
WO2010070032A1 (en) 2008-12-19 2010-06-24 Boehringer Ingelheim International Gmbh Cyclic pyrimidin-4-carboxamides as ccr2 receptor antagonists for treatment of inflammation, asthma and copd
WO2011017513A1 (en) 2009-08-07 2011-02-10 Dow Agrosciences Llc Pesticidal compositions
WO2011048525A1 (en) * 2009-10-20 2011-04-28 Pfizer Inc. Novel heteroaryl imidazoles and heteroaryl triazoles as gamma-secretase modulators
WO2012131539A1 (en) * 2011-03-31 2012-10-04 Pfizer Inc. Novel bicyclic pyridinones
US11806208B2 (en) 2014-03-21 2023-11-07 Align Technology, Inc. Orthodontic appliances with shell segments and elastic segments

Family Cites Families (82)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1419788A (en) 1972-08-02 1975-12-31 Pfizer Herbicidal method using 2-trifuluromethyl-4-quinolinols
WO1992000075A1 (en) 1990-06-29 1992-01-09 Pfizer Inc. Pyridopyrazine derivatives for treating substance abuse and addiction
US5482967A (en) 1992-09-04 1996-01-09 Takeda Chemical Industries, Ltd. Condensed heterocyclic compounds, their production and use
DE69628484T2 (de) 1995-03-24 2004-05-19 Takeda Chemical Industries, Ltd. Zyklische Verbindungen, ihre Herstellung und ihre Verwendung als Tachykininrezeptorantagonisten
AU2787299A (en) 1998-03-03 1999-09-20 Ppg Industries Ohio, Inc. Impregnated glass fiber strands and products including the same
US20020132817A1 (en) 1998-03-19 2002-09-19 Hideaki Natsugari Heterocyclic compounds, their production and use
EP1145714A4 (en) 1998-11-27 2004-12-15 Takeda Chemical Industries Ltd DRUGS
CA2498111A1 (en) 2002-09-11 2004-03-25 Merck & Co., Inc. Dihydroxypyridopyrazine-1,6-dione compounds useful as hiv integrase inhibitors
BR0315158A (pt) 2002-10-09 2005-08-16 Pfizer Prod Inc Compostos de pirazol para o tratamento de distúrbios neurodegenarativos
AU2003301439A1 (en) 2002-10-16 2004-05-04 Gilead Sciences, Inc. Pre-organized tricyclic integrase inhibitor compounds
WO2005020991A1 (en) 2003-08-21 2005-03-10 Pfizer Products, Inc. Compounds for the treatment of neurodegenerative disorders
US7572799B2 (en) 2003-11-24 2009-08-11 Pfizer Inc Pyrazolo[4,3-d]pyrimidines as Phosphodiesterase Inhibitors
US20070155731A1 (en) 2004-01-28 2007-07-05 Gabor Butora Aminocyclopentyl pyridopyrazinone modulators of chemokine receptor activity
CA2557785A1 (en) 2004-03-09 2005-10-06 Merck & Co. Inc. Hiv integrase inhibitors
BRPI0509069B8 (pt) 2004-03-23 2021-05-25 Pfizer Prod Inc compostos de imidazol e composição farmacêutica que os compreende para o tratamento de distúrbios neurodegenerativos
AU2005249363A1 (en) 2004-04-14 2005-12-15 Zhenhong R. Cai Phosphonate analogs of HIV integrase inhibitor compounds
GB0423356D0 (en) 2004-10-21 2004-11-24 Merck Sharp & Dohme Therapeutic agents
JP4982482B2 (ja) 2005-05-10 2012-07-25 メルク・シャープ・エンド・ドーム・コーポレイション Ｈｉｖインテグラ−ゼ阻害剤
EP1948614A2 (en) 2005-11-18 2008-07-30 Takeda San Diego, Inc. Glucokinase activators
JP5221144B2 (ja) 2005-11-24 2013-06-26 エーザイ・アール・アンド・ディー・マネジメント株式会社 モルホリンタイプ・シンナミド化合物
US20070117839A1 (en) 2005-11-24 2007-05-24 Eisai R&D Management Co., Ltd. Two cyclic cinnamide compound
WO2007084595A2 (en) * 2006-01-20 2007-07-26 Schering Corporation Carbocyclic and heterocyclic arylsulfones as gamma secretase inhibitors
TWI378091B (en) 2006-03-09 2012-12-01 Eisai R&D Man Co Ltd Multi-cyclic cinnamide derivatives
WO2007136714A2 (en) 2006-05-16 2007-11-29 Gilead Sciences, Inc. Integrase inhibitors
AU2007252643A1 (en) 2006-05-19 2007-11-29 Eisai R & D Management Co., Ltd. Urea type cinnamide derivative
EP2121633A2 (en) 2007-02-12 2009-11-25 Merck & Co., Inc. Piperazine derivatives for treatment of ad and related conditions
CA2676920A1 (en) 2007-02-12 2008-08-21 Merck & Co., Inc. Piperidine derivatives
US20080207900A1 (en) 2007-02-28 2008-08-28 Teiji Kimura Two cyclic oxomorphorin derivatives
WO2008137102A2 (en) 2007-05-04 2008-11-13 Torreypines Therapeutics, Inc. Methods of modulating amyloid beta and compounds useful therefor
JP5209043B2 (ja) 2007-05-07 2013-06-12 メルク・シャープ・アンド・ドーム・コーポレーション ガンマセクレターゼ調節剤
ES2358863T3 (es) 2007-05-11 2011-05-16 F. Hoffmann-La Roche Ag Hetarilanilinas como moduladores de beta-amiloide.
KR20100037053A (ko) 2007-06-01 2010-04-08 쉐링 코포레이션 감마 세크레타제 조절인자
AU2008263206A1 (en) 2007-06-01 2008-12-18 Schering Corporation Gamma secretase modulators
EP2166854A4 (en) 2007-06-13 2012-05-16 Merck Sharp & Dohme TRIAZOLE DERIVATIVES FOR THE TREATMENT OF ALZHEIMER'S DISEASE AND ASSOCIATED STATES
CA2692253A1 (en) 2007-06-29 2009-01-08 Schering Corporation Gamma secretase modulators
EP2185522A1 (en) 2007-08-06 2010-05-19 Schering Corporation Gamma secretase modulators
CA2694401C (en) 2007-08-31 2012-12-04 Eisai R&D Management Co., Ltd. Polycyclic compound
WO2009032277A1 (en) 2007-09-06 2009-03-12 Schering Corporation Gamma secretase modulators
US20100298381A1 (en) 2007-09-28 2010-11-25 Schering Corporation Gamma secretase modulators
GB0720444D0 (en) 2007-10-18 2007-11-28 Glaxo Group Ltd Novel compounds
US8487099B2 (en) 2007-11-05 2013-07-16 Merck Sharp & Dohme Corp. Gamma secretase modulators
MX2010006244A (es) * 2007-12-06 2010-12-02 Schering Corp Moduladores de gamma secretasa.
CA2708151A1 (en) 2007-12-11 2009-06-18 Schering Corporation Gamma secretase modulators
MX2010006378A (es) 2007-12-11 2010-09-07 Schering Corp Moduladores de gamma secretasa.
AU2008335709A1 (en) 2007-12-13 2009-06-18 Amgen Inc. Gamma secretase modulators
KR101244517B1 (ko) 2008-01-11 2013-03-18 에프. 호프만-라 로슈 아게 아밀로이드 베타에 대한 조절제
MX2010008700A (es) 2008-02-22 2010-08-30 Hoffmann La Roche Moduladores de beta-amiloide.
US20100137320A1 (en) 2008-02-29 2010-06-03 Schering Corporation Gamma secretase modulators
WO2009108766A1 (en) 2008-02-29 2009-09-03 Schering Corporation Gamma secretase modulators for the treatment of alzheimer ' s disease
CN102083794A (zh) 2008-05-05 2011-06-01 安姆根有限公司 作为γ分泌酶调节剂的脲化合物
FR2933700B1 (fr) * 2008-07-08 2010-07-30 Sanofi Aventis Derives de pyridino-pyridinones, leur preparation et leur application en therapeutique
TW201006801A (en) 2008-07-18 2010-02-16 Lilly Co Eli Imidazole carboxamides
WO2010019393A1 (en) 2008-08-13 2010-02-18 Merck Sharp & Dohme Corp. Pyrimidine derivatives for treatment of alzheimer's disease
WO2010019392A1 (en) 2008-08-13 2010-02-18 Merck Sharp & Dohme Corp. Purine derivatives for treatment of alzheimer's disease
EP2324009A1 (en) 2008-08-27 2011-05-25 Eisai R&D Management Co., Ltd. Process for preparing certain cinnamide compounds
AU2009301210B2 (en) 2008-10-09 2014-05-15 F. Hoffmann-La Roche Ag Modulators for amyloid beta
WO2010054064A1 (en) 2008-11-06 2010-05-14 Schering Corporation Gamma secretase modulators
JP2012508182A (ja) 2008-11-06 2012-04-05 シェーリング コーポレイション γ−セクレターゼ調節剤
CN102272133A (zh) 2008-11-06 2011-12-07 阿斯利康(瑞典)有限公司 淀粉样β的调节剂
MX2011004954A (es) 2008-11-10 2011-05-30 Hoffmann La Roche Moduladores heterociclicos de gamma-secretasa.
US20110313001A1 (en) 2008-12-16 2011-12-22 Christian Fischer Triazole derivatives for treatment of alzheimer's disease
WO2010071741A1 (en) 2008-12-16 2010-06-24 Merck Sharp & Dohme Corp. Triazole derivatives for treatment of alzheimer's disease
PA8854101A1 (es) 2008-12-18 2010-07-27 Ortho Mcneil Janssen Pharm Derivados de imidazol bicíclicos sustituidos como moduladores de gamma secretasa
CA2747750A1 (en) 2008-12-22 2010-07-01 Theodros Asberom Gamma secretase modulators
TW201034666A (en) 2008-12-22 2010-10-01 Schering Corp Gamma secretase modulators
TW201030002A (en) 2009-01-16 2010-08-16 Bristol Myers Squibb Co Bicyclic compounds for the reduction of beta-amyloid production
EP2393804B1 (en) 2009-02-06 2014-04-16 Janssen Pharmaceuticals, Inc. Novel substituted bicyclic heterocyclic compounds as gamma secretase modulators
TWI461425B (zh) * 2009-02-19 2014-11-21 Janssen Pharmaceuticals Inc 作為伽瑪分泌酶調節劑之新穎經取代的苯并唑、苯并咪唑、唑并吡啶及咪唑并吡啶衍生物類
JP2012051805A (ja) 2009-02-26 2012-03-15 Eisai R & D Management Co Ltd テトラヒドロトリアゾロピリジン誘導体の製造方法
JP2012051807A (ja) 2009-02-26 2012-03-15 Eisai R & D Management Co Ltd アリールイミダゾール化合物
JP2012051806A (ja) 2009-02-26 2012-03-15 Eisai R & D Management Co Ltd イミダゾリルピラジン誘導体
MX2011006782A (es) 2009-02-26 2011-07-20 Eisai R&D Man Co Ltd Sal de derivado de tetrahidrotriazolopiridina y un cristal de la misma.
JP2012121809A (ja) 2009-02-26 2012-06-28 Eisai R & D Management Co Ltd 多環式化合物の製造法およびその中間体
US20120053165A1 (en) 2009-03-03 2012-03-01 Pfizer Inc. Novel Phenyl Imidazoles and Phenyl Triazoles As Gamma-Secretase Modulators
AU2010341573B2 (en) * 2009-12-22 2016-10-13 Vertex Pharmaceuticals Incorporated Isoindolinone inhibitors of phosphatidylinositol 3-kinase
JP6106745B2 (ja) * 2012-05-16 2017-04-05 ヤンセン ファーマシューティカルズ，インコーポレーテッド （特に）アルツハイマー病の治療に有用な置換３，４−ジヒドロ−２Ｈ−ピリド［１，２−ａ］ピラジン−１，６−ジオン誘導体
UA110688C2 (uk) 2012-09-21 2016-01-25 Пфайзер Інк. Біциклічні піридинони
TWI614238B (zh) 2012-09-21 2018-02-11 必治妥美雅史谷比公司 雙（氟烷基）－１，４－苯并二氮呯酮化合物及其前藥
CN104918938B (zh) 2012-12-20 2017-08-15 詹森药业有限公司 新颖的作为γ分泌酶调节剂的三环3，4‑二氢‑2H‑吡啶并[1，2‑a]吡嗪‑1，6‑二酮衍生物
EP2945944B1 (en) 2013-01-17 2016-11-09 Janssen Pharmaceutica, N.V. Novel substituted pyrido-piperazinone derivatives as gamma secretase modulators
ES2742078T3 (es) 2013-10-04 2020-02-13 Pfizer Piridonas bicíclicas novedosas como moduladores de gamma-secretasa
ES2759277T3 (es) 2014-04-01 2020-05-08 Pfizer Cromeno y 1,1a,2,7b-tetrahidrociclopropa[c]cromeno piridopiracinadionionas como moduladores de gamma-secretasa

Patent Citations (52)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5750349A (en) 1993-01-25 1998-05-12 Takeda Chemical Industries Ltd. Antibodies to β-amyloids or their derivatives and use thereof
US6174884B1 (en) 1997-03-11 2001-01-16 Bayer Aktiengesellschaft 1,5-dihydro-pyrazolo[34-D]-pyrimidinone derivatives
EP0994728A1 (en) 1997-04-09 2000-04-26 Mindset, Ltd. Recombinant antibodies specific for beta-amyloid ends, dna encoding and methods of use thereof
US20030073655A1 (en) 1997-04-09 2003-04-17 Chain Daniel G. Specific antibodies to amyloid beta peptide, pharmaceutical compositions and methods of use thereof
US6235742B1 (en) 1997-10-24 2001-05-22 Pfizer Inc. 5-substituted pyrazolo[4,3-D]pyrimidin-7-ones
US20050019328A1 (en) 1997-12-02 2005-01-27 Neuralab Limited Prevention and treatment of amyloidogenic disease
US20050048049A1 (en) 1997-12-02 2005-03-03 Neuralab Limited Prevention and treatment of amyloidogenic disease
EP1257584A2 (en) 2000-02-24 2002-11-20 Washington University St. Louis Humanized antibodies that sequester amyloid beta peptide
WO2002020521A1 (de) 2000-09-11 2002-03-14 Merck Patent Gmbh Verwendung von indolderivaten zur behandlung von erkrankungen des zentralen nervensystems
US7285293B2 (en) 2000-11-03 2007-10-23 Gerardo Castillo Methods of isolating amyloid-inhibiting compounds and use of compounds isolated from Uncaria tomentosa and related plants
US20040192898A1 (en) 2001-08-17 2004-09-30 Jia Audrey Yunhua Anti-abeta antibodies
US20030195205A1 (en) 2001-11-02 2003-10-16 Pfizer Inc. PDE9 inhibitors for treating cardiovascular disorders
US20060106035A1 (en) 2002-08-23 2006-05-18 Martin Hendrix Phenyl-substituted pyrazolopyrimidines
US20060111372A1 (en) 2002-08-23 2006-05-25 Bayer Healthcare Ag Alkyl-substituted pyrazolopyrimidines
WO2004032868A2 (en) 2002-10-09 2004-04-22 Rinat Neuroscience Corp. Methods of treating alzheimer's disease using antibodies directed against amyloid beta peptide and compositions thereof
US20040220186A1 (en) 2003-04-30 2004-11-04 Pfizer Inc. PDE9 inhibitors for treating type 2 diabetes,metabolic syndrome, and cardiovascular disease
US20050043354A1 (en) 2003-06-19 2005-02-24 Pfizer Inc NK1 antagonist
WO2005025616A1 (ja) 2003-09-09 2005-03-24 Takeda Pharmaceutical Company Limited 抗体の用途
WO2005049616A1 (en) 2003-11-24 2005-06-02 Pfizer Limited 5,7-DIAMINOPYRAZOLO [4,3-d] PYRIMIDINES WITH PDE-5 INHIBITING ACTIVITY
US7115600B2 (en) 2004-02-02 2006-10-03 Pfizer Inc. Histamine-3 receptor modulators
US20050267095A1 (en) 2004-05-07 2005-12-01 Patrick Bernardelli 3- or 4-monosubstituted phenol and thiophenol derivatives useful as H3 ligands
US20050256135A1 (en) 2004-05-12 2005-11-17 Graham Lunn Tetrahydronaphthyridine derivatives
WO2006036291A2 (en) 2004-07-30 2006-04-06 Rinat Neuroscience Corp. Antibodies directed against amyloid-beta peptide and methods using same
WO2006043006A1 (fr) 2004-10-21 2006-04-27 Commissariat A L'energie Atomique Revetement nanostructure et procede de revetement
WO2006069081A2 (en) 2004-12-22 2006-06-29 Washington University In St. Louis USE OF ANTI-Aβ ANTIBODY TO TREAT TRAUMATIC BRAIN INJURY
WO2006118959A2 (en) 2005-04-29 2006-11-09 Rinat Neuroscience Corp. Antibodies directed against amyloid-beta peptide and methods using same
WO2006120552A2 (en) 2005-05-12 2006-11-16 Pfizer Inc. ANHYDROUS CRYSTALLINE FORMS OF N-[1-(2-ETHOXYETHYL)-5-(N-ETHYL-N-METHYLAMINO)-7-(4-METHYLPYRIDIN-2-yl-AMINO)-1H-PYRAZOLO[4,3-d]PYRIMIDINE-3-CARBONYL]METHANESULFONAMIDE
WO2006126083A1 (en) 2005-05-24 2006-11-30 Pharmacia & Upjohn Company Llc Pyridine [3 , 4-b] pyrazinone compounds as pde-5 inhibitors
WO2006126082A2 (en) 2005-05-24 2006-11-30 Pharmacia & Upjohn Company Llc Pyridine [3,4-b] pyrazinones as pde-5 inhibitors
WO2006126081A2 (en) 2005-05-24 2006-11-30 Pharmacia & Upjohn Company Llc Pyridino [2 , 3-b] pyrazinones as pde-5 inhibitors
WO2006136924A1 (en) 2005-06-22 2006-12-28 Pfizer Products Inc. Histamine-3 receptor antagonists
US20070060534A1 (en) 2005-06-30 2007-03-15 Threshold Pharmaceuticals, Inc. Anthracycline analogs
US20080096955A1 (en) 2005-10-27 2008-04-24 Pfizer Inc Histamine-3 receptor antagonists
US20070179175A1 (en) 2005-11-04 2007-08-02 Graham Lunn Tetrahydronaphthyridine Derivative
WO2007062332A2 (en) 2005-11-18 2007-05-31 Glaxo Group Limited Novel intermediates and their use
WO2007063385A2 (en) 2005-12-01 2007-06-07 Pfizer Products Inc. Spirocyclic amine histamine-3 receptor antagonists
WO2007069053A1 (en) 2005-12-14 2007-06-21 Pfizer Products Inc. Benzimidazole antagonists of the h-3 receptor
WO2007088450A2 (en) 2006-02-01 2007-08-09 Pfizer Products Inc. Chromane antagonist of the h-3 receptor
WO2007088462A1 (en) 2006-02-01 2007-08-09 Pfizer Products Inc. Spirochromane antagonists of the h-3 receptor
WO2007099423A1 (en) 2006-03-02 2007-09-07 Pfizer Products Inc. 1-pyrrolidine indane derivatives as histamine-3 receptor antagonists
WO2007105053A2 (en) 2006-03-13 2007-09-20 Pfizer Products Inc. Tetralines antagonists of the h-3 receptor
WO2007122466A1 (en) 2006-04-21 2007-11-01 Pfizer Products Inc. Pyridine[3,4-b]pyrazinones
US20070265332A1 (en) 2006-05-15 2007-11-15 Min Ge Antidiabetic bicyclic compounds
WO2007138431A2 (en) 2006-05-30 2007-12-06 Pfizer Products Inc. Azabicyclic ether histamine-3 antagonists
US20080176925A1 (en) 2007-01-22 2008-07-24 Pfizer Inc Toluene sulfonic acid salt of a therapeutic compound and pharmaceutical compositions thereof
WO2008150914A1 (en) 2007-05-29 2008-12-11 Sgx Pharmaceuticals, Inc. Substituted pyrrolopyridines and pyrazolopyridines as kinase modulators
US20090062529A1 (en) 2007-08-31 2009-03-05 Teiji Kimura Multi-cyclic compounds
WO2010070032A1 (en) 2008-12-19 2010-06-24 Boehringer Ingelheim International Gmbh Cyclic pyrimidin-4-carboxamides as ccr2 receptor antagonists for treatment of inflammation, asthma and copd
WO2011017513A1 (en) 2009-08-07 2011-02-10 Dow Agrosciences Llc Pesticidal compositions
WO2011048525A1 (en) * 2009-10-20 2011-04-28 Pfizer Inc. Novel heteroaryl imidazoles and heteroaryl triazoles as gamma-secretase modulators
WO2012131539A1 (en) * 2011-03-31 2012-10-04 Pfizer Inc. Novel bicyclic pyridinones
US11806208B2 (en) 2014-03-21 2023-11-07 Align Technology, Inc. Orthodontic appliances with shell segments and elastic segments

Non-Patent Citations (30)

* Cited by examiner, † Cited by third party
Title
"COMPENDIUM OF ORGANIC SYNTHETIC METHODS", vol. X, WILEY-INTERSCIENCE
A. CORSARO ET AL., J. HETEROCYCLIC CHEM., vol. 26, 1989, pages 1691 - 9
D. LAPOINTE ET AL., J. ORG. CHEM., vol. 76, 2011, pages 749 - 759
DE STROOPER, BART ET AL.: "Presenilins and y- Secretase: Structure, Function, and Role in Alzheimer's Disease", vol. 2, 2012, COLD SPRING HARB PERSPECT MED, pages: A006304
FINNIN; MORGAN, J. PHARM. SCI., vol. 88, no. 10, 1999, pages 955 - 958
G. A. WHITLOCK ET AL., BIOORG. MED. CHEM. LETT., vol. 19, 2009, pages 3118 - 3121
G. J. QUALLICH ET AL., J. ORG. CHEM., vol. 55, 1990, pages 4971 - 4973
GLENNER ET AL., J. NEUROL. SCI., vol. 94, 1989, pages 1 - 28
HAAN ET AL., CLIN. NEUROL. NEUROSURG., vol. 92, no. 4, 1990, pages 305 - 310
HAAS ET AL.: "Trafficking and proteolytic processing of APP", 2011, COLD SPRING HARBOR
HALEBLIAN, J. PHARM. SCI., vol. 64, no. 8, August 1975 (1975-08-01), pages 1269 - 1288
HOOVER; JOHN E.: "Remington's Pharmaceutical Sciences", 1975, MACK PUBLISHING CO.
J. BARLUENGA ET AL., J. ORG. CHEM., vol. 60, 1995, pages 6696 - 6699
J. T. REPINE ET AL., TETRAHEDRON LETT., vol. 48, 2007, pages 5539 - 5541
KIBBE ET AL.,: "Handbook of Pharmaceutical Excipients (3rd Ed.),", 1999, AMERICAN PHARMACEUTICAL ASSOCIATION
LIBERMAN ET AL.,: "Pharmaceutical Dosage Forms", 1980, MARCEL DECKER
M. PINESCHI ET AL., ORG. LETT., vol. 7, 2005, pages 3605 - 3607
M. R. BARBACHYN ET AL., J. MED. CHEM., vol. 46, 2003, pages 284 - 302
OLSEN ET AL., ANN. REP. MED. CHEM., vol. 42, 2007, pages 27 - 47
P. BISEL ET AL., EUR. J. ORG. CHEM., vol. 4, 1998, pages 729 - 733
R. CHINCHILLA ET AL., CHEM. SOC. REV., vol. 40, 2011, pages 5084 - 5121
S. F. MARTIN ET AL., J. ORG. CHEM., vol. 65, 2000, pages 1305 - 1318
SYNTHESIS, vol. 5, 2008, pages 795 - 799
T. A. SHEPHERD ET AL., J. MED. CHEM., vol. 45, 2002, pages 2101 - 2111
T. W. GREENE: "Protective Groups in Organic Chemistry", 1981, JOHN WILEY & SONS
T. W. GREENE; P. G. M. WUTS: "Protective Groups in Organic Chemistry", 1991, JOHN WILEY & SONS
T. W. GREENE; P. G. M. WUTS: "Protective Groups in Organic Chemistry", 1999, JOHN WILEY & SONS
T. X. M. NGUYEN ET AL., LETTERS IN ORGANIC CHEMISTRY, vol. 6, 2009, pages 630 - 636
TETRAHEDRON LETT., vol. 44, 2003, pages 3863 - 3865
TETRAHEDRON, vol. 58, 2002, pages 9633 - 9695

Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10112943B2 (en) 2012-12-20 2018-10-30 Janssen Pharmaceutica Nv Substituted imidazoles as gamma secretase modulators
US10246454B2 (en) 2013-01-17 2019-04-02 Janssen Pharmaceutica Nv Substituted 3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-diones as gamma secretase modulators
WO2015049616A1 (en) * 2013-10-04 2015-04-09 Pfizer Inc. Novel bicyclic pyridinones as gamma-secretase modulators
US10562897B2 (en) 2014-01-16 2020-02-18 Janssen Pharmaceutica Nv Substituted 3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-diones as gamma secretase modulators
JP2017512803A (ja) * 2014-04-01 2017-05-25 ファイザー・インク ガンマセクレターゼモジュレーターとしてのクロメンおよび１，１ａ，２，７Ｂ−テトラヒドロシクロプロパ［Ｃ］クロメンピリドピラジンジオン
KR102000382B1 (ko) 2015-02-03 2019-07-15 화이자 인코포레이티드 신규 시클로프로파벤조푸라닐 피리도피라진디온
CN107406445B (zh) * 2015-02-03 2019-12-24 辉瑞公司 新颖环丙苯并呋喃基吡啶并吡嗪二酮类
AU2016214102B2 (en) * 2015-02-03 2018-09-27 Pfizer Inc. Novel cyclopropabenzofuranyl pyridopyrazinediones
CN107406445A (zh) * 2015-02-03 2017-11-28 辉瑞公司 新颖环丙苯并呋喃基吡啶并吡嗪二酮类
WO2016125048A1 (en) * 2015-02-03 2016-08-11 Pfizer Inc. Novel cyclopropabenzofuranyl pyridopyrazinediones
KR20170113603A (ko) * 2015-02-03 2017-10-12 화이자 인코포레이티드 신규 시클로프로파벤조푸라닐 피리도피라진디온
EA033423B1 (ru) * 2015-02-03 2019-10-31 Pfizer Циклопропанбензофуранилпиридопиразиндионы
US9802927B2 (en) 2015-06-10 2017-10-31 Denali Therapeutics, Inc. Oxadiazine compounds and methods of use thereof
WO2017216279A1 (en) 2016-06-16 2017-12-21 F. Hoffmann-La Roche Ag Heteroaryl estrogen receptor modulators and uses thereof
US10925872B2 (en) 2016-12-16 2021-02-23 Pipeline Therapeutics, Inc. Methods of treating cochlear synaptopathy
WO2020072601A1 (en) 2018-10-02 2020-04-09 Frequency Therapeutics, Inc. Pharmaceutical compositions comprising otic therapeutic agents and related methods
WO2020072602A1 (en) 2018-10-02 2020-04-09 Frequency Therapeutics, Inc. Pharmaceutical compositions comprising otic therapeutic agents and related methods
WO2020210388A1 (en) 2019-04-08 2020-10-15 Frequency Therapeutics, Inc. Combination of chir99021 and valproic acid for treating hearing loss
US11834441B2 (en) 2019-12-06 2023-12-05 Vertex Pharmaceuticals Incorporated Substituted tetrahydrofurans as modulators of sodium channels
US11919887B2 (en) 2019-12-06 2024-03-05 Vertex Pharmaceuticals Incorporated Substituted tetrahydrofurans as modulators of sodium channels
US11827627B2 (en) 2021-06-04 2023-11-28 Vertex Pharmaceuticals Incorporated N-(hydroxyalkyl (hetero)aryl) tetrahydrofuran carboxamides as modulators of sodium channels

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